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  • 151.
    Nordquist, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Sjöquist, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Improvement of insulin response in the streptozotocin model of insulin-dependent diabetes mellitus.: Insulin response with and without a long-acting insulin treatment2009In: Animal, ISSN 1751-7311, E-ISSN 1751-732X, Vol. 3, no 5, p. 685-689Article in journal (Refereed)
    Abstract [en]

    Streptozotocin-induced diabetes mellitus (STZ-DM) in rats is a model of type 1 diabetes, which is commonly used to study diabetes, but differs from human diabetic pathophysiology in its insulin resistance, An STZ-DM rat can be administered five times the dose of insulin compared to that of a diabetic patient. Thus, attaining normoglycaemia in STZ-DM rats with insulin injections is complicated, and it involves an obvious risk of overdosing before getting a response. This study was designed to investigate whether suboptimal treatment with long-acting insulin restores insulin sensitivity in the STZ-DM rat, and thus an approach to   more closely mimic the human condition. Male Sprague-Dawley rats were made diabetic by means of a single intravenous injection of STZ (55   mg/kg body weight (BW)), resulting in an increase in blood glucose (BG)   from 6.5 +/- 0.2 to 22.5 +/- 1.0 mmol/l (P <= 0.05) within 24h. After treating the STZ-DM rats with vehicle for 14 days, BG was 26.1 +/- 1.1   mmol/l, and the response to a single injection of fast-acting insulin   (Humalog, 5 IE/kg BW) was a 23% reduction in BG. Thereafter, the rats   were treated daily with a suboptimal dose of long-acting insulin for a total of 7 days (Insulatard, 5 IE/kg per day), which resulted in a BG   level of 19.4 +/- 2.7. The response to fast-acting insulin after the   suboptimal treatment was a 61% reduction in BG. Thereafter, the animals   were vehicle-treated for another 7 days, which resulted in a response to fast-acting insulin similar to the initial values (-34%).   Furthermore, the group treated with suboptimal doses of long-acting   insulin had a longer duration of the reduction in BG (150 min, as opposed to 90 min in the vehicle-treated groups). We conclude that the   development of a decreased insulin response occurs rapidly within the   first 2 weeks after the onset of diabetes in STZ-DM rats. This leads to a brief and significantly reduced decrease in BG when tast-acting   insulin is administered, The insulin response is increased by treatment with suboptimal doses of long-acting insulin, but rapidly decreases again when treatment is withdrawn. Regular administration of suboptimal insulin doses may provide an approach to eliminate the effects of a lowered insulin response.

  • 152.
    Nordquist, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Stridh, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Effects of proinsulin C-peptide on oxygen transport, uptake and utilization in insulinopenic diabetic subjects: a review2009In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 645, p. 193-198Article in journal (Refereed)
    Abstract [en]

    Exogenous C-peptide administration has beneficial effects in many of the tissues commonly affected by diabetic complications. Diabetes-induced circulatory impairments such as decreased blood flow are prevented by C-peptide, possibly via Ca2+-mediated effects on nitric oxide release. C-peptide also improves diabetes-induced erythrocyte deformability, which likely improves oxygen availability and uptake in affected tissues. Furthermore, C-peptide prevents diabetic neuropathy via improvements of endoneural blood flow and by preventing axonal swelling. In the kidney, C-peptide normalizes the diabetes-induced increase in oxygen consumption via inhibition of the Na+/K+-ATPase. Surprisingly, C-peptide has also been shown to prevent complications in patients with type II diabetes. Taken together, these results may indicate that C-peptide treatment has the potential to reduce the prevalence of diabetic complications. In this paper, the current knowledge regarding these beneficial effects of C-peptide administered to diabetic subjects will be reviewed briefly.

  • 153.
    Nordquist, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Wahren, John
    C-Peptide: The missing link in diabetic nephropathy?2009In: The review of diabetic studies : RDS, ISSN 1614-0575, Vol. 6, no 3, p. 203-210Article in journal (Refereed)
    Abstract [en]

    Proinsulin C-peptide has been found to exert beneficial effects in many tissues affected by diabetic microvascular complications, including the kidneys. Glomerular hyperfiltration and microalbuminuria are early markers of diabetic nephropathy. C-peptide at physiological concentrations effectively reduces diabetes-induced glomerular hyperfiltration via constriction of the afferent arteriole, dilation of the efferent arteriole, and inhibition of tubular reabsorption in experimental models of type 1 diabetes. The glomerular hypertrophy and mesangial matrix expansion seen in early diabetes can be reduced or prevented by C-peptide administration, possibly via interference with TGF-beta1 and TNFalpha signaling. Several of C-peptide's reno-protective effects have been confirmed in human studies; reduced glomerular hyperfiltration and diminished urinary albumin excretion have been documented in type 1 diabetes patients receiving replacement doses of C-peptide for periods of up to 3 months. In this review, we critically summarize the current state of knowledge regarding C-peptide's renal effects, and discuss possible mechanisms of its beneficial effects in diabetic nephropathy.

  • 154.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Frontiers in Research Reviews: Kidney Oxygenation in Health and Disease Introduction2013In: Clinical and experimental pharmacology & physiology, ISSN 0305-1870, E-ISSN 1440-1681, Vol. 40, no 2, p. 104-105Article, review/survey (Refereed)
  • 155.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    The dark side of angiotensin II: direct dynamic regulation of the glomerular filtration barrier permeability to macromolecules2012In: AM J PHYSIOL-RENAL, ISSN 1931-857X, Vol. 303, no 6, p. F789-F789Article in journal (Other academic)
  • 156.
    Palm, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Fasching, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Källskog, Örjan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Nitric oxide originating from NOS1 controls oxygen utilization and electrolyte transport efficiency in the diabetic kidney2010In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 298, no 2, p. F416-F420Article in journal (Refereed)
    Abstract [en]

    Palm F, Fasching A, Hansell P, K llskog. Nitric oxide originating from NOS1 controls oxygen utilization and electrolyte transport efficiency in the diabetic kidney. Am J Physiol Renal Physiol 298: F416-F420, 2010. First published November 18, 2009; doi: 10.1152/ajprenal.00229.2009.-Nitric oxide (NO) is a potent regulator of both vascular tone and cellular oxygen consumption (QO(2)). Diabetic kidneys have reduced NO availability and increased QO(2). However, the exact nitric oxide synthase (NOS) isoform regulating QO(2), hemodynamics, and excretory function in the diabetic kidney remains unclear. We therefore investigated the effects of both selective neuronal NOS (NOS1) inhibition and nonselective NOS inhibition. Oxygen utilization, electrolyte transport efficiency [tubular Na+ transport (T-Na)/QO(2)], renal blood flow (RBF), glomerular filtration rate (GFR), and mean arterial pressure (MAP) were measured in vivo in control and streptozotocin-diabetic rats before and after administration of the selective NOS1 inhibitor S-methyl-L-thiocitrulline (SMTC) or the nonselective NOS inhibitor N-G-nitro-L-arginine methyl ester (L-NAME). Diabetic rats had higher baseline QO(2) and GFR than control rats, although RBF was similar in the groups. SMTC and L-NAME increased QO(2) and reduced T-Na/QO(2) only in the diabetic animals, whereas both inhibitors increased MAP and reduced RBF in both groups. GFR was reduced by L-NAME, but SMTC had no effect in either group. Carbachol increased RBF and decreased MAP in SMTC-treated rats, whereas it had no effect in L-NAME-treated rats, indicating that SMTC selectively inhibited NOS1. In conclusion, NO regulates RBF and GFR similarly in both control and diabetic rats. However, selective NOS1 inhibition increased QO(2) and reduced T-Na/QO(2) in the diabetic rat kidney, indicating a pivotal role of NO produced by NOS1 in maintaining control of QO(2) and tissue oxygenation in these kidneys.

  • 157.
    Palm, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Ronquist, G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Waldenström, A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Liss, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Diabetes-induced changes in renal tissue oxygen tension and cellular metabolism: Influence of polyol pathway2001In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 15, no 4, p. A447-Article in journal (Refereed)
  • 158.
    Palm, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Koeners, Maarten P.
    Univ Exeter, Sch Med, Inst Biomed & Clin Sci, Exeter, Devon, England.;Univ Bristol, Sch Physiol Pharmacol & Neurosci, Biomed Sci, Bristol, Avon, England..
    Editorial: Hypoxia in Kidney Disease2018In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, article id 485Article in journal (Other academic)
  • 159.
    Palm, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Nordquist, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Renal oxidative stress, oxygenation and hypertension2011In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 301, no 5, p. R1229-R1241Article in journal (Refereed)
    Abstract [en]

    Hypertension is closely associated with progressive kidney dysfunction, manifested as glomerulosclerosis, interstitial fibrosis, proteinuria and eventually declining glomerular filtration. The postulated mechanism for development of glomerulosclerosis is barotrauma caused by increased capillary pressure, but the reason for development of interstitial fibrosis and the subsequently reduced kidney function is less clear. However, it has been hypothesized that tissue hypoxia induces fibrogenesis and progressive renal failure. This is very interesting, since recent reports highlight several different mechanisms resulting in altered oxygen handling and availability in the hypertensive kidney. Such mechanisms include decreased renal blood flow due to increased vascular tone induced by angiotensin II that limits oxygen delivery, increased oxidative stress resulting in increased mitochondrial oxygen usage, increased oxygen usage for tubular electrolyte transport and shunting of oxygen from arterial to venous blood in preglomerular vessels. It has been shown in several studies that interventions to prevent oxidative stress and to restore kidney tissue oxygenation prevent progression of kidney dysfunction. Furthermore, inhibition of angiotensin II activity, by either blocking AT(1)-receptors or angiotensin converting enzyme, or by preventing oxidative stress by administration of antioxidants also results in improved blood pressure control. It therefore seems likely that tissue hypoxia in the hypertensive kidney contributes to progression of kidney damage and perhaps also maintaining the high blood pressure.

  • 160.
    Palm, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Nordquist, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Renal tubulointerstitial hypoxia: Cause and consequence of kidney dysfunction2011In: Clinical and experimental pharmacology & physiology, ISSN 0305-1870, E-ISSN 1440-1681, Vol. 38, no 7, p. 424-430Article in journal (Refereed)
    Abstract [en]

    1. Intrarenal oxygen availability is the balance between supply, mainly dependent on renal blood flow, and demand, determined by the basal metabolic demand and the energy-requiring tubular electrolyte transport. Renal blood flow is maintained within close limits in order to sustain stable glomerular filtration, so increased intrarenal oxygen consumption is likely to cause tissue hypoxia.

    2. The increased oxygen consumption is closely linked to increased oxidative stress, which increases mitochondrial oxygen usage and reduces tubular electrolyte transport efficiency, with both contributing to increased total oxygen consumption.

    3. Tubulointerstitial hypoxia stimulates the production of collagen I and alpha-smooth muscle actin, indicators of increased fibrogenesis. Furthermore, the hypoxic environment induces epithelial-mesenchymal transdifferentiation and aggravates fibrosis, which results in reduced peritubular blood perfusion and oxygen delivery due to capillary rarefaction.

    4. Increased oxygen consumption, capillary rarefaction and increased diffusion distance due to the increased fibrosis per se further aggravate the interstitial hypoxia.

    5. Recently, it has been demonstrated that hypoxia simulates the infiltration and maturation of immune cells, which provides an explanation for the general inflammation commonly associated with the progression of chronic kidney disease. 6. Therapies targeting interstitial hypoxia could potentially reduce the progression of chronic renal failure in millions of patients who are otherwise likely to eventually present with fully developed end-stage renal disease.

  • 161.
    Palm, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Nordquist, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Buerk, Donald G.
    Nitric oxide in the kidney: Direct measurements of bioavailable renal nitric oxide2008In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 599, p. 117-123Article in journal (Refereed)
    Abstract [en]

    Increasing efforts have been directed towards investigating the involvement of nitric oxide (NO) for normal kidney function. Recently, a crucial role of NO in the development of progressive renal dysfunction has been reported during diabetes and hypertension. Indirect estimation of renal NO production include urinary nitrite/nitrate measurements, but there are several disadvantages of indirect methods since production and bioavailability of NO rarely coincide. Thus, direct measurement of in vivo NO bioavailability is preferred, although these methods are more time consuming and require highly specialized equipment and knowledge. This review focuses on two techniques for in vivo measurement of bioavailable NO in the kidney. We have applied Whalen-type recessed NO microsensors for measurement of NO in the kidney cortex, whereas the hemoglobin-trapping technique seems to be more suitable for NO measurement in the renal medulla. Both methods are robust and reliable, and we discuss advantages and shortcomings of each method.

  • 162.
    Palm, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Onozato, Maristela
    Georgetown University.
    Welch, William J
    Georgetown University.
    Wilcox, Christopher S
    Georgetown University.
    Blood pressure, blood flow, and oxygenation in the clipped kidney of chronic 2-kidney, 1-clip rats: effects of tempol and Angiotensin blockade2010In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 55, no 2, p. 298-304Article in journal (Refereed)
    Abstract [en]

    Angiotensin II maintains renal cortical blood flow and renal oxygenation in the clipped kidney of early 2-kidney, 1-clip Goldblatt hypertensive (2K,1C) rats. The involvement of Ang II is believed to decline, whereas oxidative stress increases during the progression of 2K,1C hypertension. We investigated the hypothesis that the acute administration of drugs to inhibit reactive oxygen species (Tempol), angiotensin II type 1 receptors (candesartan), or angiotensin-converting enzyme (enalaprilat) lowers mean arterial pressure and increases kidney blood flow and oxygenation in the clipped kidney of chronic 2K,1C rats in contrast to sham controls. Twelve months after left renal artery clipping or sham, mean arterial pressure, renal cortical blood flow, and renal cortical and medullary oxygen tension were measured after acute administration of Tempol followed by enalaprilat or candesartan followed by enalaprilat. The mean arterial pressure of the 2K,1C rat was reduced by candesartan (-9%) and, more effectively, by Tempol (-35%). All of the applied treatments had similar blood pressure-lowering effects in sham rats (average: -21%). Only Tempol increased cortical blood flow (+35%) and cortical and medullary oxygen tensions (+17% and +94%, respectively) in clipped kidneys of 2K,1C rats. Administration of enalaprilat had no additional effect, except for a modest reduction in cortical blood flow in the clipped kidney of 2K,1C rats when coadministered with candesartan (-10%). In conclusion, acute administration of Tempol is more effective than candesartan in reducing the mean arterial blood pressure and improving renal blood perfusion and oxygenation in the clipped kidney of chronic 2K,1C rats.

  • 163.
    Palm, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Teerlink, Tom
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Nitric oxide and kidney oxygenation2009In: Current opinion in nephrology and hypertension, ISSN 1062-4821, E-ISSN 1473-6543, Vol. 18, no 1, p. 68-73Article, review/survey (Refereed)
    Abstract [en]

    PURPOSE OF REVIEW: The regulatory role of nitric oxide for tissue oxygen availability involves both oxygen delivery, through regulation of vascular tone, and oxygen consumption, through interference with mitochondrial respiration and tubular transport capacity. This review highlights recent findings regarding mechanisms of dysfunctional nitric oxide bioavailability in the kidney and the implications for oxygen availability and mitochondrial respiration. RECENT FINDINGS: It has been revealed that nitric oxide has several ways to influence and regulate kidney function during normal physiological conditions and that it is also involved in many of the mechanisms resulting in altered kidney function during disease. Recent reports show that nitric oxide regulates kidney oxygenation by influencing both oxygen utilization and supply. SUMMARY: Increasing evidence has accumulated during recent years for a dysfunctional nitric oxide system resulting in altered kidney oxygenation in several pathological conditions, which contributes to the development of kidney failure. We presently have extensive knowledge regarding the interplay between nitric oxide, oxygenation and kidney function; however, more effort is needed to clarify how dysfunctional nitric oxide regulation progresses to tissue hypoxia and kidney failure in various conditions, in order to identify potential therapeutic targets and develop strategies to prevent or alleviate these adverse effects and maintain adequate kidney function.

  • 164.
    Parv, Kristel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Christoffersson, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Herrera Hidalgo, Carmen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Seignez, Cedric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Elucidating the dynamics and role of peri-vascular macrophages2018In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 48, no S1, p. 82-83Article in journal (Other academic)
  • 165. Patinha, Daniela
    et al.
    Carvalho, Carla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Persson, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Pihl, Liselotte
    O'Neill, Julie
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Determinants of renal oxygen metabolism during low Na+ diet: effect of angiotensin AT1 and aldosterone receptor blockadeManuscript (preprint) (Other academic)
  • 166.
    Peng, Di
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Cupples, Claire
    Simon Fraser Univ, Dept Mol Biol & Biochem, Burnaby, BC, Canada..
    Cupples, Will
    Simon Fraser Univ, Dept Mol Biol & Biochem, Burnaby, BC, Canada..
    Mitrou, Nicholas
    Simon Fraser Univ, Dept Mol Biol & Biochem, Burnaby, BC, Canada..
    Macrophage infiltration in the kidney after prolonged surgery with anesthesia2017In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 61, no 8, p. 1010-1011Article in journal (Other academic)
  • 167. Perlewitz, A.
    et al.
    Persson, A. Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Patzak, A.
    The juxtaglomerular apparatus2012In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 205, no 1, p. 6-8Article in journal (Refereed)
  • 168.
    Persson, Malou Friederich
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Welch, William J.
    Georgetown University Medical Center, Department of Medicine, Division of Nephrology and Hypertension.
    Wilcox, Christopher S.
    Georgetown University Medical Center, Department of Medicine, Division of Nephrology and Hypertension.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Kidney function after in vivo gene silencing of Uncoupling Protein-2 in streptozotocin-induced diabetic rats2013In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 765, p. 217-223Article in journal (Refereed)
    Abstract [en]

    Kidney uncoupling protein 2 (UCP-2) increases in streptozotocin-induced diabetes, resulting in mitochondria uncoupling, i.e., increased oxygen consumption unrelated to active transport. The present study aimed to investigate the role of UCP-2 for normal and diabetic kidney function utilizing small interference RNA (siRNA) to reduce protein expression. Diabetic animals had increased glomerular filtration rate and kidney oxygen consumption, resulting in decreased oxygen tension and transported sodium per consumed oxygen. UCP-2 protein levels decreased 2 and 50% after UCP-2 siRNA administration in control and diabetic animals respectively. Kidney function was unaffected by in vivo siRNA-mediated gene silencing of UCP-2. The reason for the lack of effect of reducing UCP-2 is presently unknown but may involve compensatory mitochondrial uncoupling by the adenosine nucleotide transporter.

  • 169. Persson, P. B.
    et al.
    Liss, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Lagerqvist, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Response to 'Iodixanol vs ioxaglate for preventing contrast nephropathy: Who is the winner?'2007In: Kidney International, ISSN 0085-2538, E-ISSN 1523-1755, Vol. 71, no 8, p. 828-829Article in journal (Refereed)
  • 170.
    Persson, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Aspects of Regulation of GFR and Tubular Function in the Diabetic Kidney: Roles of Adenosine, Nitric Oxide and Oxidative Stress2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Diabetic nephropathy is the main cause for initiation of renal replacement therapy and early symptoms in patients include increased glomerular filtration rate (GFR), decreased oxygen tension and albuminuria, followed by a progressive decline in GFR and loss of kidney function. Experimental models of diabetes display increased GFR, decreased tissue oxygenation and nitric oxide bioavailability. These findings are likely to be intertwined in a mechanistic pathway to kidney damage and this thesis investigated their roles in the development of diabetic nephropathy. In vivo, diabetes-induced oxidative stress stimulates renal tubular Na+ transport and in vitro, proximal tubular cells from diabetic rats display increased transport-dependent oxygen consumption, demonstrating mechanisms contributing to decreased kidney oxygenation. In control animals, endogenous adenosine reduces vascular resistance of the efferent arteriole via adenosine A2-receptors resulting in reduced filtration fraction. However, in diabetes, adenosine A2-signalling is dysfunctional resulting in increased GFR via increased filtration fraction. This is caused by reduced adenosine A2a receptor-mediated vasodilation of efferent arterioles. The lack of adenosine-signaling in diabetes is likely due to reduced local adenosine concentration since adenosine A2a receptor activation reduced GFR only in diabetic animals by efferent arteriolar vasodilation. Furthermore, sub-optimal insulin treatment also alleviates increased filtration pressure in diabetes. However, this does not affect GFR due to a simultaneously induction of renal-blood flow dependent regulation of GFR by increasing the filtration coefficient. In diabetes, there is decreased bioavailability of nitric oxide, resulting in alterations that may contribute to diabetes-induced hyperfiltration and decreased oxygenation. Interestingly, increased plasma concentration of l-arginine, the substrate for nitric oxide production, prevents the development of increased GFR and proteinuria, but not increased oxygen consumption leading to sustained intra-renal hypoxia in diabetes. This thesis concludes that antioxidant treatment directed towards the NADPH oxidase as well maneuvers to promote nitric oxide production is beneficial in diabetic kidneys but is targeting different pathways i.e. transport-dependent oxygen consumption in the proximal tubule by NADPH oxidase inhibition and intra-renal hemodynamics after increased plasma l-arginine. Also, the involvement and importance of efferent arteriolar resistance in the development of diabetes-induced hyperfiltration via reduced adenosine A2a signaling is highlighted.

    List of papers
    1. NADPH oxidase inhibition reduces tubular sodium transport and improves kidney oxygenation in diabetes
    Open this publication in new window or tab >>NADPH oxidase inhibition reduces tubular sodium transport and improves kidney oxygenation in diabetes
    2012 (English)In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 302, no 12, p. R1443-R1449Article in journal (Refereed) Published
    Abstract [en]

    Sustained hyperglycemia is associated with increased oxidative stress resulting in decreased intrarenal oxygen tension (Po-2) due to increased oxygen consumption (Qo(2)). Chronic blockade of the main superoxide radicals producing system, the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, normalizes Qo(2) by isolated proximal tubular cells (PTC) and reduces proteinuria in diabetes. The aim was to investigate the effects of acute NADPH oxidase inhibition on tubular Na+ transport and kidney Po-2 in vivo. Glomerular filtration rate (GFR), renal blood flow (RBF), filtration fraction (FF), Na+ excretion, fractional Li+ excretion, and intrarenal Po-2 was measured in control and streptozotocin-diabetic rats during baseline and after acute NADPH oxidase inhibition using apocynin. The effects on tubular transporters were investigated using freshly isolated PTC. GFR was increased in diabetics compared with controls (2.2 +/- 0.3 vs. 1.4 +/- 0.1 ml.min (-1).kidney (-1)). RBF was similar in both groups, resulting in increased FF in diabetics. Po-2 was reduced in cortex and medulla in diabetic kidneys compared with controls (34.4 +/- 0.7 vs. 42.5 +/- 1.2 mmHg and 15.7 +/- 1.2 vs. 25.5 +/- 2.3 mmHg, respectively). Na+ excretion was increased in diabetics compared with controls (24.0 +/- 4.7 vs. 9.0 +/- 2.0 mu m.min(-1).kidney(-1)). In controls, all parameters were unaffected. However, apocynin increased Na+ excretion (+112%) and decreased fractional lithium reabsorption (-10%) in diabetics, resulting in improved cortical (+14%) and medullary (+28%) Po-2. Qo(2) was higher in PTC isolated from diabetic rats compared with control. Apocynin, dimethylamiloride, and ouabain reduced Qo(2), but the effects of combining apocynin with either dimethylamiloride or ouabain were not additive. In conclusion, NADPH oxidase inhibition reduces tubular Na+ transport and improves intrarenal Po-2 in diabetes.

    Keywords
    apocynin, dimethylamiloride, ouabain, oxygen tension, oxidative stress, proximal tubular cells, rat, streptozotocin
    National Category
    Physiology
    Identifiers
    urn:nbn:se:uu:diva-177608 (URN)10.1152/ajpregu.00502.2011 (DOI)000305424000008 ()
    Available from: 2012-07-17 Created: 2012-07-17 Last updated: 2018-01-12Bibliographically approved
    2. Insulin induces the correlation between renal blood flow and glomerular filtration rate in diabetes: implications for mechanisms causing hyperfiltration
    Open this publication in new window or tab >>Insulin induces the correlation between renal blood flow and glomerular filtration rate in diabetes: implications for mechanisms causing hyperfiltration
    Show others...
    2012 (English)In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 303, no 1, p. R39-R47Article in journal (Refereed) Published
    Abstract [en]

    Glomerular filtration rate (GFR) and renal blood flow (RBF) are normally kept constant via renal autoregulation. However, early diabetes results in increased GFR and the potential mechanisms are debated. Tubuloglomerular feedback (TGF) inactivation, with concomitantly increased RBF, is proposed but challenged by the finding of glomerular hyperfiltration in diabetic adenosine A(1) receptor-deficient mice, which lack TGF. Furthermore, we consistently find elevated GFR in diabetes with only minor changes in RBF. This may relate to the use of a lower streptozotocin dose, which produces a degree of hyperglycemia, which is manageable without supplemental suboptimal insulin administration, as has been used by other investigators. Therefore, we examined the relationship between RBF and GFR in diabetic rats with (diabetes + insulin) and without suboptimal insulin administration (untreated diabetes). As insulin can affect nitric oxide (NO) release, the role of NO was also investigated. GFR, RBF, and glomerular filtration pressures were measured. Dynamic RBF autoregulation was examined by transfer function analysis between arterial pressure and RBF. Both diabetic groups had increased GFR (+60-67%) and RBF (+20-23%) compared with controls. However, only the diabetes + insulin group displayed a correlation between GFR and RBF (R-2 = 0.81, P < 0.0001). Net filtration pressure was increased in untreated diabetes compared with both other groups. The difference between untreated and insulin-treated diabetic rats disappeared after administering N-omega-nitro-L-arginine methyl ester to inhibit NO synthase and subsequent NO release. In conclusion, mechanisms causing diabetes-induced glomerular hyperfiltration are animal model-dependent. Supplemental insulin administration results in a RBF-dependent mechanism, whereas elevated GFR in untreated diabetes is mediated primarily by a tubular event. Insulin-induced NO release partially contributes to these differences.

    Keywords
    insulin, net filtraton pressure, N-omega-nitro-L-arginine methyl ester
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-179030 (URN)10.1152/ajpregu.00582.2011 (DOI)000306186600005 ()
    Available from: 2012-08-06 Created: 2012-08-06 Last updated: 2017-12-07Bibliographically approved
    3. Adenosine A2 receptor-mediated regulation of renal hemodynamics and glomerular filtration rate is abolished in diabetes
    Open this publication in new window or tab >>Adenosine A2 receptor-mediated regulation of renal hemodynamics and glomerular filtration rate is abolished in diabetes
    2013 (English)In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 765, p. 225-230Article in journal (Refereed) Published
    Abstract [en]

    Alterations in glomerular filtration rate (GFR) are one of the earliest indications of altered kidney function in diabetes. Adenosine regulates GFR through tubuloglomerular feedback mechanism acting on adenosine A1 receptor. In addition, adenosine can directly regulate vascular tone by acting on A1 and A2 receptors expressed in afferent and efferent arterioles. Opposite to A1 receptors, A2 receptors mediate vasorelaxation. This study investigates the involvement of adenosine A2 receptors in regulation of renal blood flow (RBF) and GFR in control and diabetic kidneys. GFR was measured by inulin clearance and RBF by a transonic flow probe placed around the renal artery. Measurements were performed in isoflurane-anesthetized normoglycemic and alloxan-diabetic C57BL/6 mice during baseline and after acute administration of 3,7-dimethyl-1-propargylxanthine (DMPX), a selective A2 receptor antagonist. GFR and RBF were lower in diabetic mice compared to control (258 ± 61 vs. 443 ± 33 μl min -1 and 1,083 ± 51 vs. 1,405 ± 78 μl min -1). In control animals, DMPX decreased RBF by-6%, whereas GFR increased +44%. DMPX had no effects on GFR and RBF in diabetic mice. Sodium excretion increased in diabetic mice after A2 receptor blockade (+78%). In conclusion, adenosine acting on A2 receptors mediates an efferent arteriolar dilatation which reduces filtration fraction (FF) and maintains GFR within normal range in normoglycemic mice. However, this regulation is absent in diabetic mice, which may contribute to reduced oxygen availability in the diabetic kidney.

    Place, publisher, year, edition, pages
    Springer-Verlag New York, 2013
    Keywords
    Alloxan, C57BL/6, DMPX, Renal blood flow
    National Category
    Medical and Health Sciences Basic Medicine
    Identifiers
    urn:nbn:se:uu:diva-186810 (URN)10.1007/978-1-4614-4989-8_31 (DOI)000339280100032 ()9781461447719 (ISBN)
    Available from: 2012-12-12 Created: 2012-11-29 Last updated: 2018-01-12
    4. Reduced adenosine A2a receptor–mediated efferent arteriolar vasodilation contributes to diabetes-induced glomerular hyperfiltration
    Open this publication in new window or tab >>Reduced adenosine A2a receptor–mediated efferent arteriolar vasodilation contributes to diabetes-induced glomerular hyperfiltration
    2015 (English)In: Kidney International, ISSN 0085-2538, E-ISSN 1523-1755, Vol. 87, no 1, p. 109-115Article in journal (Refereed) Published
    Abstract [en]

    Diabetes is associated with increased risk for development of kidney disease, and an increased glomerular filtration rate is an early indication of altered kidney function. Here we determine whether reduced adenosine A2a receptor-mediated vasodilation of the efferent arteriole contributes to the increased glomerular filtration rate in diabetes. The glomerular filtration rate, renal blood flow, and proximal tubular stop flow pressure were investigated in control and streptozotocin-diabetic rats during baseline and after administration of the adenosine A2a receptor antagonist ZM241385 or the adenosine A2a receptor agonist CGS21680. The diabetes-induced glomerular hyperfiltration was reduced by 24% following A2a receptor stimulation but was unaffected by A2a receptor inhibition. Contrarily, glomerular filtration rate in controls increased by 22% after A2a receptor inhibition and was unaffected by A2a stimulation. The increased glomerular filtration rate after A2a receptor inhibition in controls and decreased glomerular filtration rate after A2a receptor activation in diabetics were caused by increased and decreased stop flow pressure, respectively. None of the interventions affected renal blood flow. Thus, the normal adenosine A2a receptor-mediated tonic vasodilation of efferent arterioles is abolished in the diabetic kidney. This causes increased efferent arteriolar resistance resulting in increased filtration fraction and hyperfiltration.

    Keywords
    kidney, CGS21680, renal blood flow, glomerular filtration rate, net filtration pressure
    National Category
    Physiology
    Research subject
    Physiology; Medical Science
    Identifiers
    urn:nbn:se:uu:diva-195428 (URN)10.1038/ki.2014.219 (DOI)000346977900014 ()
    Funder
    Swedish Research Council
    Available from: 2013-02-25 Created: 2013-02-25 Last updated: 2018-01-11Bibliographically approved
    5. L-Citrulline, But Not L-Arginine, Prevents Diabetes Mellitus–Induced Glomerular Hyperfiltration and Proteinuria in Rat
    Open this publication in new window or tab >>L-Citrulline, But Not L-Arginine, Prevents Diabetes Mellitus–Induced Glomerular Hyperfiltration and Proteinuria in Rat
    Show others...
    2014 (English)In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 64, no 2, p. 323-329Article in journal (Refereed) Published
    Abstract [en]

    Diabetes mellitus–induced oxidative stress causes increased renal oxygen consumption and intrarenal tissue hypoxia. Nitric oxide is an important determinant of renal oxygen consumption and electrolyte transport efficiency. The present study investigates whether l-arginine or l-citrulline to promote nitric oxide production prevents the diabetes mellitus–induced kidney dysfunction. Glomerular filtration rate, renal blood flow, in vivo oxygen consumption, tissue oxygen tension, and proteinuria were investigated in control and streptozotocin-diabetic rats with and without chronic l-arginine or l-citrulline treatment for 3 weeks. Untreated and l-arginine–treated diabetic rats displayed increased glomerular filtration rate (2600±162 versus 1599±127 and 2290±171 versus 1739±138 µL/min per kidney), whereas l-citrulline prevented the increase (1227±126 versus 1375±88 µL/min per kidney). Filtration fraction was increased in untreated diabetic rats because of the increase in glomerular filtration rate but not in l-arginine– or l-citrulline–treated diabetic rats. Urinary protein excretion was increased in untreated and l-arginine–treated diabetic rats (142±25 versus 75±7 and 128±7 versus 89±7 µg/min per kidney) but not in diabetic rats administered l-citrulline (67±7 versus 61±5 µg/min per kidney). The diabetes mellitus–induced tissue hypoxia, because of elevated oxygen consumption, was unaltered by any of the treatments. l-citrulline administered to diabetic rats increases plasma l-arginine concentration, which prevents the diabetes mellitus–induced glomerular hyperfiltration, filtration fraction, and proteinuria, possibly by a vascular effect.

    National Category
    Physiology Basic Medicine
    Research subject
    Medical Science; Physiology
    Identifiers
    urn:nbn:se:uu:diva-195487 (URN)10.1161/HYPERTENSIONAHA.114.03519 (DOI)000339120700023 ()24866144 (PubMedID)
    Available from: 2013-02-25 Created: 2013-02-25 Last updated: 2018-01-11Bibliographically approved
  • 171.
    Persson, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Fasching, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Acute intrarenal angiotensin (1-7) infusion decreases diabetes-induced glomerular hyperfiltration but increases kidney oxygen consumption in the rat2019In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 226, no 1, article id e13254Article in journal (Refereed)
    Abstract [en]

    Aim: Common kidney alterations early after the onset of insulinopenic diabetes include glomerular hyperfiltration, increased oxygen consumption and tissue hypoxia. Increased activity of the renin-angiotensin-aldosterone system (RAAS) has been implicated in most of these early alterations. The RAAS peptide angiotensin (1-7) has the potential to modulate RAAS-mediated alterations in kidney function. Thus, the aim of the present study was to determine the acute effects of angiotensin (1-7) in the kidney of insulinopenic type 1 diabetic rat and the results compared to that of normoglycaemic controls.

    Methods: Renal haemodynamics and oxygen homeostasis were measured 3 weeks after administration of streptozotocin before and after acute intrarenal infusion of angiotensin (1-7) at a dose of 400 ng min(-1).

    Results: Arterial pressure and renal blood flow were similar between groups and not affected by exogenous angiotensin (1-7). Diabetics presented with glomerular hyperfiltration, increased urinary sodium excretion and elevated kidney oxygen consumption. Angiotensin (1-7) infusion normalized glomerular filtration, increased urinary sodium excretion, decreased proximal tubular reabsorption, and elevated kidney oxygen consumption even further. The latter resulting in tubular electrolyte transport inefficiency. Angiotensin (1-7) did not affect tissue oxygen tension and had no significant effects in controls on any of the measured parameters.

    Conclusion: Diabetes results in increased responsiveness to elevated levels of angiotensin (1-7) which is manifested as inhibition of tubular sodium transport and normalization of glomerular filtration. Furthermore, elevated angiotensin (1-7) levels increase kidney oxygen consumption in the diabetic kidney even further which affects tubular electrolyte transport efficiency negatively.

  • 172.
    Persson, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Fasching, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Teerlink, Tom
    Vrije Univ Amsterdam, Med Ctr, Dept Clin Chem, Amsterdam, Netherlands.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Cellular transport of L-Arginine determines renal medullary blood flow in control rats, but not in diabetic rats despite enhanced cellular uptake capacity2017In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 312, no 2, p. F278-F283Article in journal (Refereed)
    Abstract [en]

    Diabetes mellitus is associated with decreased nitric oxide bioavailability thereby affecting renal blood flow regulation. Previous reports have demonstrated that cellular uptake of L-arginine is rate limiting for nitric oxide production, and that plasma L-arginine concentration is decreased in diabetes. We therefore investigated if regional renal blood flow regulation is affected by cellular L-arginine uptake in streptozotocin-induced diabetic rats. Rats were anesthetized with thiobutabarbital and left kidney was exposed. Total, cortical and medullary renal blood flow was investigated before and after renal artery infusion of increasing doses of either L-homoarginine to inhibit cellular uptake of L-arginine, or L-NAME to inhibit nitric oxide synthase. L-homoarginine infusion did not affect total or cortical blood flow in any of the groups, but caused a dose-dependent reduction in medullary blood flow. L-NAME decreased total, cortical and medullary blood flow in both groups. However, the reductions in medullary blood flow in response to both L-homoarginine and L-NAME were more pronounced in the control groups compared to the diabetic groups. Isolated cortical tubular cells displayed similar L-arginine uptake capacity whereas medullary tubular cells isolated from diabetic rats had increased L-arginine uptake capacity. Diabetics had reduced L-arginine concentrations in plasma and medullary tissue but increased L-arginine concentration in cortical tissue. In conclusion, the reduced L-arginine availability in plasma and medullary tissue in diabetes results in reduced nitric oxide-mediated regulation of renal medullary hemodynamics. Cortical blood flow regulation displays less dependency on extracellular L-arginine and the upregulated cortical tissue L-arginine may protect cortical hemodynamics in diabetes.

  • 173.
    Persson, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Fasching, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Teerlink, Tom
    Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    L-Citrulline, But Not L-Arginine, Prevents Diabetes Mellitus–Induced Glomerular Hyperfiltration and Proteinuria in Rat2014In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 64, no 2, p. 323-329Article in journal (Refereed)
    Abstract [en]

    Diabetes mellitus–induced oxidative stress causes increased renal oxygen consumption and intrarenal tissue hypoxia. Nitric oxide is an important determinant of renal oxygen consumption and electrolyte transport efficiency. The present study investigates whether l-arginine or l-citrulline to promote nitric oxide production prevents the diabetes mellitus–induced kidney dysfunction. Glomerular filtration rate, renal blood flow, in vivo oxygen consumption, tissue oxygen tension, and proteinuria were investigated in control and streptozotocin-diabetic rats with and without chronic l-arginine or l-citrulline treatment for 3 weeks. Untreated and l-arginine–treated diabetic rats displayed increased glomerular filtration rate (2600±162 versus 1599±127 and 2290±171 versus 1739±138 µL/min per kidney), whereas l-citrulline prevented the increase (1227±126 versus 1375±88 µL/min per kidney). Filtration fraction was increased in untreated diabetic rats because of the increase in glomerular filtration rate but not in l-arginine– or l-citrulline–treated diabetic rats. Urinary protein excretion was increased in untreated and l-arginine–treated diabetic rats (142±25 versus 75±7 and 128±7 versus 89±7 µg/min per kidney) but not in diabetic rats administered l-citrulline (67±7 versus 61±5 µg/min per kidney). The diabetes mellitus–induced tissue hypoxia, because of elevated oxygen consumption, was unaltered by any of the treatments. l-citrulline administered to diabetic rats increases plasma l-arginine concentration, which prevents the diabetes mellitus–induced glomerular hyperfiltration, filtration fraction, and proteinuria, possibly by a vascular effect.

  • 174.
    Persson, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Friederich-Persson, Malou
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Fasching, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Inagi, Reiko
    University of Tokyo Graduate School of Medicine, Tokyo, Japan.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Adenosine A2 a receptor stimulation prevents proteinuria in diabetic rats by promoting an anti-inflammatory phenotype without affecting oxidative stress2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 214, no 3, p. 311-318Article in journal (Refereed)
    Abstract [en]

    AIM: Diabetic patients are at increased risk for kidney disease. There is presently no clinical treatment available that effectively protects kidney function in diabetics. The present study investigates if chronic stimulation of the adenosine A2a receptor (A2a AR) protects kidney function in insulinopenic diabetic rats.

    METHODS: Streptozotocin-induced diabetic rats and corresponding controls were chronically treated with the adenosine A2a AR agonist CGS21680 throughout the four-week diabetes duration. Kidney function was thereafter investigated and urine and plasma samples were collected for analysis of protein, oxidative stress and inflammatory markers.

    RESULTS: Glomerular filtration rate, renal blood flow, filtration fraction and diabetes-induced kidney hypoxia were all unaffected by chronic A2a AR stimulation. Furthermore, diabetic rats had increased oxidative stress, which was further increased by chronic A2a AR stimulation. However, the 10-fold increased urinary protein excretion observed in the diabetic rats was completely prevented by chronic A2a AR stimulation. These beneficial effects were accompanied by reduced levels of the pro-inflammatory TNF-α and increased levels of the anti-inflammatory IL-10 as well as decreased infiltration of macrophages, glomerular damage and basement membrane thickness.

    CONCLUSION: Chronic A2a AR stimulation prevents proteinuria and glomerular damage in experimental diabetes via an anti-inflammatory mechanism independent of oxidative stress and kidney hypoxia.

  • 175.
    Persson, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Adenosine A2 receptor-mediated regulation of renal hemodynamics and glomerular filtration rate is abolished in diabetes2013In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 765, p. 225-230Article in journal (Refereed)
    Abstract [en]

    Alterations in glomerular filtration rate (GFR) are one of the earliest indications of altered kidney function in diabetes. Adenosine regulates GFR through tubuloglomerular feedback mechanism acting on adenosine A1 receptor. In addition, adenosine can directly regulate vascular tone by acting on A1 and A2 receptors expressed in afferent and efferent arterioles. Opposite to A1 receptors, A2 receptors mediate vasorelaxation. This study investigates the involvement of adenosine A2 receptors in regulation of renal blood flow (RBF) and GFR in control and diabetic kidneys. GFR was measured by inulin clearance and RBF by a transonic flow probe placed around the renal artery. Measurements were performed in isoflurane-anesthetized normoglycemic and alloxan-diabetic C57BL/6 mice during baseline and after acute administration of 3,7-dimethyl-1-propargylxanthine (DMPX), a selective A2 receptor antagonist. GFR and RBF were lower in diabetic mice compared to control (258 ± 61 vs. 443 ± 33 μl min -1 and 1,083 ± 51 vs. 1,405 ± 78 μl min -1). In control animals, DMPX decreased RBF by-6%, whereas GFR increased +44%. DMPX had no effects on GFR and RBF in diabetic mice. Sodium excretion increased in diabetic mice after A2 receptor blockade (+78%). In conclusion, adenosine acting on A2 receptors mediates an efferent arteriolar dilatation which reduces filtration fraction (FF) and maintains GFR within normal range in normoglycemic mice. However, this regulation is absent in diabetic mice, which may contribute to reduced oxygen availability in the diabetic kidney.

  • 176.
    Persson, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    NADPH oxidase inhibition reduces tubular sodium transport and improves kidney oxygenation in diabetes2012In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 302, no 12, p. R1443-R1449Article in journal (Refereed)
    Abstract [en]

    Sustained hyperglycemia is associated with increased oxidative stress resulting in decreased intrarenal oxygen tension (Po-2) due to increased oxygen consumption (Qo(2)). Chronic blockade of the main superoxide radicals producing system, the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, normalizes Qo(2) by isolated proximal tubular cells (PTC) and reduces proteinuria in diabetes. The aim was to investigate the effects of acute NADPH oxidase inhibition on tubular Na+ transport and kidney Po-2 in vivo. Glomerular filtration rate (GFR), renal blood flow (RBF), filtration fraction (FF), Na+ excretion, fractional Li+ excretion, and intrarenal Po-2 was measured in control and streptozotocin-diabetic rats during baseline and after acute NADPH oxidase inhibition using apocynin. The effects on tubular transporters were investigated using freshly isolated PTC. GFR was increased in diabetics compared with controls (2.2 +/- 0.3 vs. 1.4 +/- 0.1 ml.min (-1).kidney (-1)). RBF was similar in both groups, resulting in increased FF in diabetics. Po-2 was reduced in cortex and medulla in diabetic kidneys compared with controls (34.4 +/- 0.7 vs. 42.5 +/- 1.2 mmHg and 15.7 +/- 1.2 vs. 25.5 +/- 2.3 mmHg, respectively). Na+ excretion was increased in diabetics compared with controls (24.0 +/- 4.7 vs. 9.0 +/- 2.0 mu m.min(-1).kidney(-1)). In controls, all parameters were unaffected. However, apocynin increased Na+ excretion (+112%) and decreased fractional lithium reabsorption (-10%) in diabetics, resulting in improved cortical (+14%) and medullary (+28%) Po-2. Qo(2) was higher in PTC isolated from diabetic rats compared with control. Apocynin, dimethylamiloride, and ouabain reduced Qo(2), but the effects of combining apocynin with either dimethylamiloride or ouabain were not additive. In conclusion, NADPH oxidase inhibition reduces tubular Na+ transport and improves intrarenal Po-2 in diabetes.

  • 177.
    Persson, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Reduced adenosine A2a receptor–mediated efferent arteriolar vasodilation contributes to diabetes-induced glomerular hyperfiltration2015In: Kidney International, ISSN 0085-2538, E-ISSN 1523-1755, Vol. 87, no 1, p. 109-115Article in journal (Refereed)
    Abstract [en]

    Diabetes is associated with increased risk for development of kidney disease, and an increased glomerular filtration rate is an early indication of altered kidney function. Here we determine whether reduced adenosine A2a receptor-mediated vasodilation of the efferent arteriole contributes to the increased glomerular filtration rate in diabetes. The glomerular filtration rate, renal blood flow, and proximal tubular stop flow pressure were investigated in control and streptozotocin-diabetic rats during baseline and after administration of the adenosine A2a receptor antagonist ZM241385 or the adenosine A2a receptor agonist CGS21680. The diabetes-induced glomerular hyperfiltration was reduced by 24% following A2a receptor stimulation but was unaffected by A2a receptor inhibition. Contrarily, glomerular filtration rate in controls increased by 22% after A2a receptor inhibition and was unaffected by A2a stimulation. The increased glomerular filtration rate after A2a receptor inhibition in controls and decreased glomerular filtration rate after A2a receptor activation in diabetics were caused by increased and decreased stop flow pressure, respectively. None of the interventions affected renal blood flow. Thus, the normal adenosine A2a receptor-mediated tonic vasodilation of efferent arterioles is abolished in the diabetic kidney. This causes increased efferent arteriolar resistance resulting in increased filtration fraction and hyperfiltration.

  • 178.
    Persson, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Tubular reabsorption and diabetes-induced glomerular hyperfiltration2010In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 200, no 1, p. 3-10Article, review/survey (Refereed)
    Abstract [en]

    Elevated glomerular filtration rate (GFR) is a common observation in early diabetes mellitus and closely correlates with the progression of diabetic nephropathy. Hyperfiltration has been explained to be the result of a reduced load of sodium and chloride passing macula densa, secondarily to an increased proximal reabsorption of glucose and sodium by the sodium-glucose co-transporters. This results in an inactivation of the tubuloglomerular feedback (TGF), leading to a reduced afferent arteriolar vasoconstriction and subsequently an increase in GFR. This hypothesis has recently been questioned due to the observation that adenosine A(1)-receptor knockout mice, previously shown to lack a functional TGF mechanism, still display a pronounced hyperfiltration when diabetes is induced. Leyssac demonstrated in the 1960s (Acta Physiol Scand58, 1963:236) that GFR and proximal reabsorption can work independently of each other. Furthermore, by the use of micropuncture technique a reduced hydrostatic pressure in Bowman's space or in the proximal tubule of diabetic rats has been observed. A reduced pressure in Bowman's space will increase the pressure gradient over the filtration barrier and can contribute to the development of diabetic hyperfiltration. When inhibiting proximal reabsorption with a carbonic anhydrase inhibitor, GFR decreases and proximal tubular pressure increases. Measuring intratubular pressure allows a sufficient time resolution to reveal that net filtration pressure decreases before TGF is activated which highlights the importance of intratubular pressure as a regulator of GFR. Taken together, these results imply that the reduced intratubular pressure observed in diabetes might be crucial for the development of glomerular hyperfiltration.

  • 179.
    Persson, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Hypoxia-inducible factor activation in diabetic kidney disease.2017In: Current opinion in nephrology and hypertension, ISSN 1062-4821, E-ISSN 1473-6543, Vol. 26, no 5, p. 345-350Article, review/survey (Refereed)
    Abstract [en]

    PURPOSE OF REVIEW:

    Tissue hypoxia is present in kidneys from diabetic patients and constitutes a central pathway to diabetic kidney disease (DKD). This review summarizes regulation of hypoxia inducible factor (HIF) and interventions towards the same for treatment of DKD.

    RECENT FINDINGS:

    In the hypoxic diabetic kidney, HIF activity and the effects of HIF signaling seem to be cell-specific. In mesangial cells, elevated glucose levels induce HIF activity by a hypoxia-independent mechanism. Elevated HIF activity in glomerular cells promotes glomerulosclerosis and albuminuria, and inhibition of HIF protects glomerular integrity. However, tubular HIF activity is suppressed and HIF activation protects mitochondrial function and prevents development of diabetes-induced tissue hypoxia, tubulointerstitial fibrosis and proteinuria. No clinical treatment targeting kidney hypoxia is currently available, but development of prolyl hydroxylase inhibitors to promote HIF activity to treat renal anemia could potentially also target diabetes-induced kidney hypoxia.

    SUMMARY:

    Increasing HIF activity in the diabetic kidney may possess a novel target for treatment of DKD by improving kidney oxygen homeostasis. However, HIF-mediated glomerulosclerosis may be a concern. The kidney outcomes from the ongoing clinical trials using prolyl hydroxylase inhibitors may provide additional insights into the complex role of HIF signaling in the diabetic kidney.

  • 180.
    Petersson, Joel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Carlström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Schreiber, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Christoffersson, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Jägare, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Roos, Stefan
    Jansson, Emmelie Å.
    Persson, A. Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Lundberg, Jon O.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Gastroprotective and blood pressure lowering effects of dietary nitrate are abolished by an antiseptic mouthwash2009In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 46, no 8, p. 1068-1075Article in journal (Refereed)
    Abstract [en]

    Recently, it has been suggested that the supposedly inert nitrite anion is reduced in vivo to form bioactive nitric oxide with physiological and therapeutic implications in the gastrointestinal and cardiovascular systems. Intake of nitrate-rich food such as vegetables results in increased levels of circulating nitrite in a process suggested to involve nitrate-reducing bacteria in the oral cavity. Here we investigated the importance of the oral microflora and dietary nitrate in regulation of gastric mucosal defense and blood pressure. Rats were treated twice daily with a commercial antiseptic mouthwash while they were given nitrate-supplemented drinking water. The mouthwash greatly reduced the number of nitrate-reducing oral bacteria and as a consequence, nitrate-induced increases in gastric NO and circulating nitrite levels were markedly reduced. With the mouthwash the observed nitrate-induced increase in gastric mucus thickness was attenuated and the gastroprotective effect against an ulcerogenic compound was lost. Furthermore, the decrease in systemic blood pressure seen during nitrate supplementation was now absent. These results suggest that oral symbiotic bacteria modulate gastrointestinal and cardiovascular function via bioactivation of salivary nitrate. Excessive use of antiseptic mouthwashes may attenuate the bioactivity of dietary nitrate.

  • 181.
    Petersson, Joel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Schreiber, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Hansson, Gunnar C.
    Gendler, Sandra J.
    Velcich, Anna
    Lundberg, Jon O.
    Roos, Stefan
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Importance and regulation of the colonic mucus barrier in a mouse model of colitis2011In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 300, no 2, p. G327-G333Article in journal (Refereed)
    Abstract [en]

    The colonic mucus layer serves as an important barrier and prevents colonic bacteria from invading the mucosa and cause inflammation. The regulation of colonic mucus secretion is poorly understood. The aim of this study was to investigate the role of the mucus barrier in induction of colitis. Furthermore, regulation of mucus secretion by luminal bacterial products was studied. The colon of anesthetized Muc2−/−, Muc1−/−, wild-type (wt), and germ-free mice was exteriorized, the mucosal surface was visualized, and mucus thickness was measured with micropipettes. Colitis was induced by DSS (dextran sodium sulfate, 3%, in drinking water), and disease activity index (DAI) was assessed daily. The colonic mucosa of germ-free and conventionally housed mice was exposed to the bacterial products LPS (lipopolysaccharide) and PGN (peptidoglycan). After DSS induction of colitis, the thickness of the firmly adherent mucus layer was significantly thinner after 5 days and onward, which paralleled the increment of DAI. Muc2−/− mice, which lacked firmly adherent mucus, were predisposed to colitis, whereas Muc1−/− mice were protected with significantly lower DAI by DSS compared with wt mice. The mucus barrier increased in Muc1−/− mice in response to DSS, whereas significantly fewer T cells were recruited to the inflamed colon. Mice housed under germ-free conditions had an extremely thin adherent colonic mucus layer, but when exposed to bacterial products (PGN or LPS) the thickness of the adherent mucus layer was quickly restored to levels observed in conventionally housed mice. This study demonstrates a correlation between decreasing mucus barrier and increasing clinical symptoms during onset of colitis. Mice lacking colonic mucus (Muc2−/−) were hypersensitive to DSS-induced colitis, whereas Muc1−/− were protected, probably through the ability to increase the mucus barrier but also by decreased T cell recruitment to the afflicted site. Furthermore, the ability of bacteria to regulate the thickness of the colonic mucus was demonstrated.

  • 182. Petri, Björn
    et al.
    Kaur, Jaswinder
    Long, Elizabeth M.
    Li, Hang
    Parsons, Sean A.
    Butz, Stefan
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Vestweber, Dietmar
    Patel, Kamala D.
    Robbins, Stephen M.
    Kubes, Paul
    Endothelial LSP1 is involved in endothelial dome formation, minimizing vascular permeability changes during neutrophil transmigration in vivo2011In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 117, no 3, p. 942-952Article in journal (Refereed)
    Abstract [en]

    The endothelium actively participates in neutrophil migration out of the vasculature via dynamic, cytoskeleton-dependent rearrangements leading to the formation of transmigratory cups in vitro, and to domes that completely surround the leukocyte in vivo. Leukocyte-specific protein 1 (LSP1), an F-actin-binding protein recently shown to be in the endothelium, is critical for effective transmigration, although the mechanism has remained elusive. Herein we show that endothelial LSP1 is expressed in the nucleus and cytosol of resting endothelial cells and associates with the cytoskeleton upon endothelial activation. Two-photon microscopy revealed that endothelial LSP1 was crucial for the formation of endothelial domes in vivo in response to neutrophil chemokine keratinocyte-derived chemokine (KC) as well as in response to endogenously produced chemokines stimulated by cytokines (tumor necrosis factor α [TNFα] or interleukin-1β [IL-1β]). Endothelial domes were significantly reduced in Lsp1-/- compared with wildtype (WT) mice. Lsp1-/- animals not only showed impaired neutrophil emigration after KC and TNFα stimulation, but also had disproportionate increases in vascular permeability. We demonstrate that endothelial LSP1 is recruited to the cytoskeleton in inflammation and plays an important role in forming endothelial domes thereby regulating neutrophil transendothelial migration. The permeability data may underscore the physiologic relevance of domes and the role for LSP1 in endothelial barrier integrity.

  • 183. Petri, Björn
    et al.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Kubes, Paul
    The physiology of leukocyte recruitment: an in vivo perspective2008In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 180, no 10, p. 6439-6446Article, review/survey (Refereed)
    Abstract [en]

    The mechanisms of leukocyte recruitment have been studied extensively in vitro and have shed light on the basic molecular structure-function relationship of adhesion and signaling molecules involved in this essential immune response. This review will summarize how these in vitro observations extend to leukocyte behavior in inflamed blood vessels in the microcirculation. We highlight physiological results that might not have been predicted from in vitro systems. Special attention is placed on the physiology of rolling, adhesion, and intralumenal crawling in blood vessels. The importance of the glycocalyx, secondary tethers, shear, and the microenvironment are discussed. Docking structures forming rings of adhesion molecules together with a novel endothelial dome-like structure in vivo during transmigration are highlighted. Transcellular and paracellular emigration out of inflamed blood vessels is also discussed. The last section highlights leukocyte recruitment in some organs that do not always follow the accepted paradigm of leukocyte recruitment.

  • 184.
    Pettersson, Ulrika Sofia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Christoffersson, Gustaf
    Massena, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Ahl, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Henriksnäs, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Increased Recruitment but Impaired Function of Leukocytes during Inflammation in Mouse Models of Type 1 and Type 2 Diabetes2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 7, p. e22480-Article in journal (Refereed)
    Abstract [en]

    Background

    Patients suffering from diabetes show defective bacterial clearance. This study investigates the effects of elevated plasma glucose levels during diabetes on leukocyte recruitment and function in established models of inflammation.

    Methodology/Principal Findings

    Diabetes was induced in C57Bl/6 mice by intravenous alloxan (causing severe hyperglycemia), or by high fat diet (moderate hyperglycemia). Leukocyte recruitment was studied in anaesthetized mice using intravital microscopy of exposed cremaster muscles, where numbers of rolling, adherent and emigrated leukocytes were quantified before and during exposure to the inflammatory chemokine MIP-2 (0.5 nM). During basal conditions, prior to addition of chemokine, the adherent and emigrated leukocytes were increased in both alloxan- (62±18% and 85±21%, respectively) and high fat diet-induced (77±25% and 86±17%, respectively) diabetes compared to control mice. MIP-2 induced leukocyte emigration in all groups, albeit significantly more cells emigrated in alloxan-treated mice (15.3±1.0) compared to control (8.0±1.1) mice. Bacterial clearance was followed for 10 days after subcutaneous injection of bioluminescent S. aureus using non-invasive IVIS imaging, and the inflammatory response was assessed by Myeloperoxidase-ELISA and confocal imaging. The phagocytic ability of leukocytes was assessed using LPS-coated fluorescent beads and flow cytometry. Despite efficient leukocyte recruitment, alloxan-treated mice demonstrated an impaired ability to clear bacterial infection, which we found correlated to a 50% decreased phagocytic ability of leukocytes in diabetic mice.

    Conclusions/Significance

    These results indicate that reduced ability to clear bacterial infections observed during experimentally induced diabetes is not due to reduced leukocyte recruitment since sustained hyperglycemia results in increased levels of adherent and emigrated leukocytes in mouse models of type 1 and type 2 diabetes. Instead, decreased phagocytic ability observed for leukocytes isolated from diabetic mice might account for the impaired bacterial clearance.

  • 185.
    Pettersson, Ulrika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Waldén, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Female Mice are Protected against High-Fat Diet Induced Metabolic Syndrome and Increase the Regulatory T Cell Population in Adipose Tissue2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 9, p. e46057-Article in journal (Refereed)
    Abstract [en]

    Sex differences in obesity-induced complications such as type 2 diabetes have been reported. The aim of the study was to pinpoint the mechanisms resulting in different outcome of female and male mice on a high-fat diet (HFD). Mice fed control or HFD were monitored for weight, blood glucose, and insulin for 14 weeks. Circulating chemokines, islet endocrine function and blood flow, as well as adipose tissue populations of macrophages and regulatory T-lymphocytes (T-reg) were thereafter assessed. Despite similar weight (43.8 +/- 1.0 and 40.2 +/- 1.5 g, respectively), male but not female mice developed hyperinsulinemia on HFD as previously described (2.5 +/- 0.7 and 0.5 +/- 0.1 pmol/l, respectively) consistent with glucose intolerance. Male mice also exhibited hypertrophic islets with intact function in terms of insulin release and blood perfusion. Low-grade, systemic inflammation was absent in obese female but present in obese male mice (IL-6 and mKC, males: 77.4 +/- 17 and 1795 +/- 563; females: 14.6 +/- 4.9 and 240 +/- 22 pg/ml), and the population of inflammatory macrophages was increased in intra-abdominal adipose tissues of high-fat-fed male but not female mice. In contrast, the anti-inflammatory T-reg cell population increased in the adipose tissue of female mice in response to weight gain, while the number decreased in high-fat-fed male mice. In conclusion, female mice are protected against HFD-induced metabolic changes while maintaining an anti-inflammatory environment in the intra-abdominal adipose tissue with expanded T-reg cell population, whereas HFD-fed male mice develop adipose tissue inflammation, glucose intolerance, hyperinsulinemia, and islet hypertrophy.

  • 186.
    Phillipson, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Heit, Bryan
    Parsons, Sean A
    Petri, Björn
    Mullaly, Sarah C
    Colarusso, Pina
    Gower, R Michael
    Neely, Gregory
    Simon, Scott I
    Kubes, Paul
    Vav1 is essential for mechanotactic crawling and migration of neutrophils out of the inflamed microvasculature2009In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 182, no 11, p. 6870-6878Article in journal (Refereed)
    Abstract [en]

    Mac-1-dependent crawling is a new step in the leukocyte recruitment cascade that follows LFA-1-dependent adhesion and precedes emigration. Neutrophil adhesion via LFA-1 has been shown to induce cytoskeletal reorganization through Vav1-dependent signaling, and the current study investigates the role of Vav1 in the leukocyte recruitment process in vivo with particular attention to the events immediately downstream of LFA-1-dependent adhesion. Intravital and spinning-disk-confocal microscopy was used to investigate intravascular crawling in relation to endothelial junctions in vivo in wild-type and Vav1(-/-) mice. Adherent wild-type neutrophils almost immediately began crawling perpendicular to blood flow via Mac-1 until they reached an endothelial junction where they often changed direction. This pattern of perpendicular, mechanotactic crawling was recapitulated in vitro when shear was applied. In sharp contrast, the movement of Vav1(-/-) neutrophils was always in the direction of flow and appeared more passive as if the cells were dragged in the direction of flow in vivo and in vitro. More than 80% of Vav1(-/-) neutrophils moved independent of Mac-1 and could be detached with LFA-1 Abs. An inability to release the uropod was frequently noted for Vav1(-/-) neutrophils, leading to greatly elongated tails. The Vav1(-/-) neutrophils failed to stop or follow junctions and ultimately detached, leading to fewer emigrated neutrophils. The Vav1(-/-) phenotype resulted in fewer neutrophils recruited in a relevant model of infectious peritonitis. Clearly, Vav1 is critical for the complex interplay between LFA-1 and Mac-1 that underlies the programmed intravascular crawling of neutrophils.

  • 187.
    Phillipson, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Henriksnäs, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Holstad, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sandler, Stellan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Inducible nitric oxide synthase is involved in acid-induced gastric hyperemia in rats and mice2003In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 285, no 1, p. G154-G162Article in journal (Refereed)
    Abstract [en]

    The role of different isoforms of nitric oxide synthase (NOS) in the gastric mucosal hyperemia, induced by 155 mM luminal hydrochloric acid (pH approximately 0.8) without a barrier breaker, was investigated. Rats were anesthetized with Inactin (120 mg/kg ip), and mice were anesthetized with Forene (2.2% in 40% oxygen gas at 150 ml/min); the gastric mucosa was exteriorized. Gastric mucosal blood flow was measured with laser-Doppler flowmetry (LDF) in rats treated with Nomega-nitro-l-arginine (l-NNA; unspecific NOS inhibitor), l-N6-(1-iminoethyl)lysine [l-NIL; inducible (i) NOS inhibitor], or S-methyl-l-thiocitrulline [SMTC; neuronal (n) NOS inhibitor], 10 mg/kg, followed by 3 mg. kg-1. h-1 iv, in iNOS-deficient (-/-) and nNOS(-/-) mice. mRNA was isolated from the gastric mucosa in iNOS(-/-) and wild-type (wt) mice, and real-time RT-PCR was performed. The effect of 155 mM acid on gastric mucosal permeability was determined by measuring the clearance of 51Cr-EDTA from blood to lumen. LDF increased by 48 +/- 13% during 155 mM HCl luminally, an increase that was abolished by l-NNA, SMTC, or l-NIL. In iNOS wt mice, LDF increased by 33 +/- 8% during luminal acid. The blood flow increase was attenuated substantially in iNOS(-/-) mice. RT-PCR revealed iNOS mRNA expression in the gastric mucosa in the iNOS wt groups. The blood flow increase in response to acid was not abolished in nNOS(-/-) mice (nNOS-sufficient mice, 39 +/- 18%; heterozygous mice, 25 +/- 19%; -/- mice, 19 +/- 7%). Mucosal permeability was transiently increased during 155 mM HCl. The results suggest that iNOS is constitutively expressed in the gastric mucosa and is involved in acid-induced hyperemia, suggesting a novel role for iNOS in gastric mucosal protection.

  • 188.
    Phillipson, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Johansson, Malin E V
    Henriksnäs, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Petersson, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Gendler, Sandra J
    Sandler, Stellan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Persson, A Erik G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Hansson, Gunnar C
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    The gastric mucus layers: constituents and regulation of accumulation2008In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 295, no 4, p. G806-G812Article in journal (Refereed)
    Abstract [en]

    The mucus layer continuously covering the gastric mucosa consists of a loosely adherent layer that can be easily removed by suction, leaving a firmly adherent mucus layer attached to the epithelium. These two layers exhibit different gastroprotective roles; therefore, individual regulation of thickness and mucin composition were studied. Mucus thickness was measured in vivo with micropipettes in anesthetized mice [isoflurane; C57BL/6, Muc1-/-, inducible nitric oxide synthase (iNOS)-/-, and neuronal NOS (nNOS)-/-] and rats (inactin) after surgical exposure of the gastric mucosa. The two mucus layers covering the gastric mucosa were differently regulated. Luminal administration of PGE(2) increased the thickness of both layers, whereas luminal NO stimulated only firmly adherent mucus accumulation. A new gastroprotective role for iNOS was indicated since iNOS-deficient mice had thinner firmly adherent mucus layers and a lower mucus accumulation rate, whereas nNOS did not appear to be involved in mucus secretion. Downregulation of gastric mucus accumulation was observed in Muc1-/- mice. Both the firmly and loosely adherent mucus layers consisted of Muc5ac mucins. In conclusion, this study showed that, even though both the two mucus layers covering the gastric mucosa consist of Muc5ac, they are differently regulated by luminal PGE(2) and NO. A new gastroprotective role for iNOS was indicated since iNOS-/- mice had a thinner firmly adherent mucus layer. In addition, a regulatory role of Muc1 was demonstrated since downregulation of gastric mucus accumulation was observed in Muc1-/- mice.

  • 189.
    Phillipson, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Kaur, Jaswinder
    Colarusso, Pina
    Ballantyne, Christie M
    Kubes, Paul
    Endothelial domes encapsulate adherent neutrophils and minimize increases in vascular permeability in paracellular and transcellular emigration2008In: PLoS ONE, ISSN 1932-6203, Vol. 3, no 2, p. e1649-Article in journal (Refereed)
    Abstract [en]

    Local edema, a cardinal sign of inflammation associates closely with neutrophil emigration. Neutrophil emigration has been described to occur primarily through endothelial junctions (paracellular) and more rarely directly through endothelial cells (transcellular). Recently, we reported that unlike in wild-type (wt) mice, Mac-1-/- (CD11b) neutrophils predominantly emigrated transcellularly and was significantly delayed taking 20-30 min longer than the paracellular emigration (wt). In the present study we noted significant anatomical disruption of the endothelium and hypothesized that transcellular emigration would greatly increase vascular permeability. Surprisingly, despite profound disruption of the endothelial barrier as the neutrophils moved through the cells, the changes in vascular permeability during transcellular emigration (Mac-1-/-) were not increased more than in wt mice. Instead increased vascular permeability completely tracked the number of emigrated cells and as such, permeability changes were delayed in Mac-1-/- mice. However, by 60 min neutrophils from both sets of mice were emigrating in large numbers. Electron-microscopy and spinning disk multichannel fluorescence confocal microscopy revealed endothelial docking structures that progressed to dome-like structures completely covering wt and Mac-1-/- neutrophils. These domes completely enveloped the emigrating neutrophils in both wt and Mac-1-/- mice making the mode of emigration underneath these structures extraneous to barrier function. In conclusion, predominantly paracellular versus predominantly transcellular emigration does not affect vascular barrier integrity as endothelial dome-like structures retain barrier function.

  • 190.
    Phillipson, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Kubes, Paul
    Univ Calgary, Snyder Inst Infect Immun & Inflammat, Calgary, AB T2N 4N1, Canada;Univ Calgary, Dept Physiol & Pharmacol, Calgary, AB T2N 4N1, Canada.
    The Healing Power of Neutrophils2019In: Trends in immunology, ISSN 1471-4906, E-ISSN 1471-4981, Vol. 40, no 7, p. 635-647Article, review/survey (Refereed)
    Abstract [en]

    Neutrophils promptly accumulate in large numbers at sites of tissue injury. Injuries to the skin or mucosae disrupt barriers against the external environment, and the bactericidal actions of neutrophils are important in preventing microbial invasion. Neutrophils have also been associated with exacerbated inflammation, for example in non-healing wounds or in conditions such as inflammatory bowel disease (IBD). However, additional neutrophil functions important for angiogenesis and tissue restoration have been uncovered in models of sterile and ischemic injury, as well as in tumors. These functions are also relevant in healing skin and mucosal wounds, and can be impaired in conditions associated with non-healing wounds, such as diabetes. Here, we discuss our current understanding of neutrophil contributions to healing, and how the latter can be compromised in disease.

  • 191.
    Phillipson, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Kubes, Paul
    The neutrophil in vascular inflammation2011In: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 17, no 11, p. 1381-1390Article, review/survey (Refereed)
    Abstract [en]

    Here we focus on how neutrophils have a key regulatory role in vascular inflammation. Recent studies using advanced imaging techniques have yielded new insights into the mechanisms by which neutrophils contribute to defense against bacterial infections and also against sterile injury. In these settings, neutrophils are recruited by various mechanisms depending on the situation. We also describe how these processes may be disrupted in systemic infections, with a particular emphasis on mouse models of sepsis. Neutrophils are often immobilized in the lungs and liver during systemic infections, and this immobilization may be a mechanism through which bacteria can evade the innate immune response or allow neutrophils to form neutrophil extracellular traps that trap and kill bacteria in blood. The platelet is also an important player in sepsis, and we describe how it collaborates with neutrophils in the formation of neutrophil extracellular traps.

  • 192.
    Pihl, Liselotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Nangaku, Masaomi
    Inagi, Reiko
    Liss, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Nordquist, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Pre-existing hypoxia sensitizes the kidney to an ischemia-reperfusion insult2014In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, no 1, article id 890.10Article in journal (Other academic)
  • 193.
    Pihl, Liselotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Persson, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Fasching, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    DiBona, Gerald F.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Insulin induces the correlation between renal blood flow and glomerular filtration rate in diabetes: implications for mechanisms causing hyperfiltration2012In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 303, no 1, p. R39-R47Article in journal (Refereed)
    Abstract [en]

    Glomerular filtration rate (GFR) and renal blood flow (RBF) are normally kept constant via renal autoregulation. However, early diabetes results in increased GFR and the potential mechanisms are debated. Tubuloglomerular feedback (TGF) inactivation, with concomitantly increased RBF, is proposed but challenged by the finding of glomerular hyperfiltration in diabetic adenosine A(1) receptor-deficient mice, which lack TGF. Furthermore, we consistently find elevated GFR in diabetes with only minor changes in RBF. This may relate to the use of a lower streptozotocin dose, which produces a degree of hyperglycemia, which is manageable without supplemental suboptimal insulin administration, as has been used by other investigators. Therefore, we examined the relationship between RBF and GFR in diabetic rats with (diabetes + insulin) and without suboptimal insulin administration (untreated diabetes). As insulin can affect nitric oxide (NO) release, the role of NO was also investigated. GFR, RBF, and glomerular filtration pressures were measured. Dynamic RBF autoregulation was examined by transfer function analysis between arterial pressure and RBF. Both diabetic groups had increased GFR (+60-67%) and RBF (+20-23%) compared with controls. However, only the diabetes + insulin group displayed a correlation between GFR and RBF (R-2 = 0.81, P < 0.0001). Net filtration pressure was increased in untreated diabetes compared with both other groups. The difference between untreated and insulin-treated diabetic rats disappeared after administering N-omega-nitro-L-arginine methyl ester to inhibit NO synthase and subsequent NO release. In conclusion, mechanisms causing diabetes-induced glomerular hyperfiltration are animal model-dependent. Supplemental insulin administration results in a RBF-dependent mechanism, whereas elevated GFR in untreated diabetes is mediated primarily by a tubular event. Insulin-induced NO release partially contributes to these differences.

  • 194.
    Pittner, János
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Endothelial Nitric Oxide in the Control of Glomerular Hemodynamics2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The afferent arteriole of the kidney is a unique vascular segment: it is the effector of the renal hemodynamic autoregulation. The use of the isolated, perfused juxtamedullary nephron preparation makes it possible to visualize the afferent arteriole while preserving its tissue surroundings and the functional integrity of the nephron.

    The author has developed a method to measure and evaluate fluorescence signals from the afferent arteriolar endothelium in this preparation and has measured endothelial intracellular calcium levels and endothelial nitric oxide production during various conditions in this model. Albumin, a common ingredient of perfusion media, has been shown to have considerable capacity to scavenge nitric oxide. Scavenging properties of the perfusion media are important in setting a "working level" of nitric oxide in the wall of the afferent arteriole. To examine the role of nitric oxide in renal autoregulation, different luminal pressures in the entire autoregulatory pressure range have been used and the endothelial calcium and luminal pressure were found to be inversely related. Nitric oxide production of the endothelium was enhanced by increases in perfusion pressure. Applying existing models of the production and diffusion of nitric oxide in blood vessels and by inserting measured vascular parameters, a mathematical model was created to describe pressure profile, shear stress, nitric oxide production and diffusion relationships and vascular reactivity in the afferent arteriole.

    In conclusion, nitric oxide, a major physiological dilator, plays a paramount role in renal autoregulation and afferent arteriolar vasoreactivity. Effective vessel wall nitric oxide levels are modulated by the luminal scavenging. Shear stress enhances the production of nitric oxide, by stimulating the endothelial nitric oxide synthase through non-calcium mediated mechanisms.

  • 195.
    Qi, Haiyun
    et al.
    Aarhus Univ, Dept Clin Med, MR Res Ctr, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark..
    Nielsen, Per M.
    Aarhus Univ, Dept Clin Med, MR Res Ctr, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark..
    Schroeder, Marie
    Aarhus Univ, Dept Clin Med, MR Res Ctr, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark..
    Bertelsen, Lotte B.
    Aarhus Univ, Dept Clin Med, MR Res Ctr, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark..
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Laustsen, Christoffer
    Aarhus Univ, Dept Clin Med, MR Res Ctr, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark..
    Acute renal metabolic effect of metformin assessed with hyperpolarised MRI in rats2018In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, no 2, p. 445-454Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis

    Metformin inhibits hepatic mitochondrial glycerol phosphate dehydrogenase, thereby increasing cytosolic lactate and suppressing gluconeogenesis flux in the liver. This inhibition alters cytosolic and mitochondrial reduction–oxidation (redox) potential, which has been reported to protect organ function in several disease states including diabetes. In this study, we investigated the acute metabolic and functional changes induced by metformin in the kidneys of both healthy and insulinopenic Wistar rats used as a model of diabetes.

    Methods

    Diabetes was induced by intravenous injection of streptozotocin, and kidney metabolism in healthy and diabetic animals was investigated 4 weeks thereafter using hyperpolarised 13C-MRI, Clark-type electrodes and biochemical analysis.

    Results

    Metformin increased renal blood flow, but did not change total kidney oxygen consumption. In healthy rat kidneys, metformin increased [1-13C]lactate production and reduced mitochondrial [1-13C]pyruvate oxidation (decreased the 13C-bicarbonate/[1-13C]pyruvate ratio) within 30 min of administration. Corresponding alterations to indices of mitochondrial, cytosolic and whole-cell redox potential were observed. Pyruvate oxidation was maintained in the diabetic rats, suggesting that the diabetic state abrogates metabolic reprogramming caused by metformin.

    Conclusions/interpretation

    This study demonstrates that metformin-induced acute metabolic alterations in healthy kidneys favoured anaerobic metabolism at the expense of aerobic metabolism. The results suggest that metformin directly alters the renal redox state, with elevated renal cytosolic redox states as well as decreased mitochondrial redox state. These findings suggest redox biology as a novel target to eliminate the renal complications associated with metformin treatment in individuals with impaired renal function.

  • 196.
    Risberg, Anitha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Hormones and fluid balance during pregnancy, labor and post partum2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The aim of this thesis was to determine any association between plasma oxytocin and vasopressin concentrations and renal water and sodium excretion during normal pregnancy. In addition to investigate changes in concentrations of estradiol, progesterone, oxytocin, cortisol, and glucose in the blood before and in the nearest hours after delivery and if treatment with oxytocin affected these concentrations and the fluid balance during the different stages of labour.

    Oxytocin, vasopressin, estradiol, progesterone, and cortisol were analysed in blood plasma or serum by radioimmunoassay or ELISA: serum glucose, and osmolality, and sodium in plasma and urine were  analysed by standard laboratory techniques.

    Fifty-seven women were studied during pregnancy and fifty-one during parturition and post partum. The low plasma vasopressin and increasing plasma oxytocin concentrations with unchanged water and sodium excretion indicate that oxytocin assists vasopressin in concentrating urine during pregnancy.

    Plasma vasopressin concentration continued to be low during parturition and post partum. Urine flow and concentration was unrelated to changes in plasma sodium concentration, indicating regulation of fluid balance during parturition was different to the non-gravid state. Women with weak myometrial contractions during parturition (slow progress of labour) reacted differently than women with normal parturition and a group of women with fast progress of labour. The group with slow labour had lower serum estradiol concentration in the latency phase and became hyponatremic. Pulsatile and continuous oxytocin infusions were both effective in the treatment of slow progress of labour. A lower amount of oxytocin was needed to affect delivery when given as pulsatile infusion.

    Serum cortisol and glucose concentrations were high during labour and cortisol level remained elevated after delivery and glucose concentration reached the highest levels (12 mmol/L) at the same time. Insulin resistance together with the long time of elevated cortisol concentration partly explained the high glucose concentration. In conclusion, fluid balance is not regulated according to the usual sensitive osmotic and volumetric influence on vasopressin release from the neurohypophysis during pregnancy and parturition. Parturition involves a change from one demanding condition, pregnancy, to another, lactation. Parturition and the hours directly after delivery are a turbulent period involving considerable stress.

    List of papers
    1. Relationship between urinary albumin and albumin/creatinine ratio during normal pregnancy and pre-eclampsia.
    Open this publication in new window or tab >>Relationship between urinary albumin and albumin/creatinine ratio during normal pregnancy and pre-eclampsia.
    Show others...
    2004 (English)In: Scand J Clin Lab Invest, ISSN 0036-5513, Vol. 64, no 1, p. 17-23Article in journal (Other scientific) Published
    Abstract [en]

    Risberg A, Larsson A, Olsson K, Lyrenäs S, Sjöquist M.

    Department of Nursing and Health Sciences, Mid Sweden University, Ornsköldsvik, Sweden. anitha.risberg@mh.se

    Pre-eclampsia is a serious complication of pregnancy and it is important to detect the condition as early as possible. Albuminuria is an important symptom of pre-eclampsia and repeated urine analyses to screen for the condition are part of the standard antenatal care. The purpose of this study was to investigate whether measurement of the urine albumin/creatinine ratio in spot samples could be a complement to the dipstick method and could reduce the need for 24-h urine collections. Urine samples were collected for 24 h in weeks 12, 24 and 36 of pregnancy from both normotensive women and women who developed hypertension or who had pregnancy-induced hypertension (PIH) when they entered the study. The 24-h albumin excretion was significantly correlated to the albumin/creatinine ratio in all measurements (Pearson correlation coefficient). In week 12, the values were: n = 44, r = 0.964, p < 0.001 (normotensive group) and in the PIH group: n = 8, r = 0.789, p < 0.05. In week 24, the correlation values were r = 1.0 and p < 0.001 in both the normotensive group (n = 41) and in the PIH group (n = 11). In week 36 the correlation values were r = 0.791 and p < 0.001 in the normotensive group (n = 39) and r = 1.0 and p < 0.001 in the PIH group (n = 16). Microalbuminuria was defined as urine albumin excretion higher than 30 mg/24 h and this corresponded to an albumin/creatinine ratio of 2.9. Microalbuminuria was found in three persons in the PIH group and in two persons in the normotensive group. Overt albuminuria (> 300 mg/24 h) was found in one of the 46 normotensive women (2%) and in 3 of the 19 PIH women (16%). In all these women the high albumin values had been detected by using the albumin/creatinine ratio method. In conclusion, it has been found that the albumin excretion in urine correlates significantly to the albumin/creatinine ratio during pregnancy. The urinary albumin/creatinine ratio appears to be a good alternative to the dipstick method and to 24-h urine collections.

    PMID: 15025425 [PubMed - indexed for MEDLINE]

    Keywords
    Adult, Albuminuria/*diagnosis/urine, Blood Pressure, Creatinine/*urine, Female, Humans, Pre-Eclampsia/*diagnosis, Pregnancy
    Identifiers
    urn:nbn:se:uu:diva-12865 (URN)15025425 (PubMedID)
    Available from: 2008-08-01 Created: 2008-08-01 Last updated: 2011-01-12
    2. Plasma vasopressin, oxytocin, estradiol, and progesterone related to water and sodium excretion in normal pregnancy and gestational hypertension
    Open this publication in new window or tab >>Plasma vasopressin, oxytocin, estradiol, and progesterone related to water and sodium excretion in normal pregnancy and gestational hypertension
    2009 (English)In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 88, no 6, p. 639-646Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVE: To investigate associations between plasma oxytocin and vasopressin concentrations and renal water and sodium excretion during normal pregnancy in comparison with gestational hypertension. DESIGN: A prospective open trial conducted in the 12th, 24th, and 36th weeks of gestation. SETTINGS: Seven antenatal clinics in Sweden. PARTICIPANTS: Thirty-seven normotensive women, 15 women with gestational hypertension, and five women with mild preeclampsia. MAIN OUTCOME MEASURES: Hormones were analyzed with radioimmunoassay. Albumin, osmolality, sodium, and urea were analyzed by routine methods. RESULTS: Blood pressure was elevated in the hypertensive women and body mass index in mild preeclampsia from week 12. Renal sodium excretion did not differ between groups or weeks and mean renal free water clearance was negative. In normotensive women, the vasopressin concentration was 1.1+/-0.2 (week 12) and 0.7+/-0.1 pmol/L (week 36: p = 0.053). In hypertensive women, vasopressin concentration was 1.7+/-1.0 pmol/L, week 12, and 0.7+/-0.1 pmol/L in week 36 (ns). In normotensive women, oxytocin concentration increased from 23+/-1 pmol/L in week 12 to 48+/-3 pmol/L in week 36 (p<0.001). Corresponding values in hypertensive women were 36+/-11 (week 12) and 55+/-5 pmol/L (week 36: ns). In all groups, plasma estradiol concentration increased. Plasma progesterone increased until week 24 in normotensive and hypertensive women with further increase in normotensive women. CONCLUSIONS: The low plasma vasopressin and increasing plasma oxytocin concentrations with unchanged water and sodium excretion indicate that oxytocin assists vasopressin in concentrating urine during pregnancy.

    Keywords
    BMI, gestation, oxytocin, vasopressin, water excretion
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-105261 (URN)10.1080/00016340902919002 (DOI)000267201800004 ()19412798 (PubMedID)
    Available from: 2009-06-02 Created: 2009-06-02 Last updated: 2017-12-13Bibliographically approved
  • 197.
    Risberg, Anitha
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Olsson, Kerstin
    Lyrenäs, Sven
    Sjöquist, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Plasma vasopressin, oxytocin, estradiol, and progesterone related to water and sodium excretion in normal pregnancy and gestational hypertension2009In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 88, no 6, p. 639-646Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate associations between plasma oxytocin and vasopressin concentrations and renal water and sodium excretion during normal pregnancy in comparison with gestational hypertension. DESIGN: A prospective open trial conducted in the 12th, 24th, and 36th weeks of gestation. SETTINGS: Seven antenatal clinics in Sweden. PARTICIPANTS: Thirty-seven normotensive women, 15 women with gestational hypertension, and five women with mild preeclampsia. MAIN OUTCOME MEASURES: Hormones were analyzed with radioimmunoassay. Albumin, osmolality, sodium, and urea were analyzed by routine methods. RESULTS: Blood pressure was elevated in the hypertensive women and body mass index in mild preeclampsia from week 12. Renal sodium excretion did not differ between groups or weeks and mean renal free water clearance was negative. In normotensive women, the vasopressin concentration was 1.1+/-0.2 (week 12) and 0.7+/-0.1 pmol/L (week 36: p = 0.053). In hypertensive women, vasopressin concentration was 1.7+/-1.0 pmol/L, week 12, and 0.7+/-0.1 pmol/L in week 36 (ns). In normotensive women, oxytocin concentration increased from 23+/-1 pmol/L in week 12 to 48+/-3 pmol/L in week 36 (p<0.001). Corresponding values in hypertensive women were 36+/-11 (week 12) and 55+/-5 pmol/L (week 36: ns). In all groups, plasma estradiol concentration increased. Plasma progesterone increased until week 24 in normotensive and hypertensive women with further increase in normotensive women. CONCLUSIONS: The low plasma vasopressin and increasing plasma oxytocin concentrations with unchanged water and sodium excretion indicate that oxytocin assists vasopressin in concentrating urine during pregnancy.

  • 198.
    Rolny, Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Mazzone, Massimiliano
    Tugues, Sònia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Laoui, Damya
    Johansson, Irja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Coulon, Cathy
    Squadrito, Mario Leonardo
    Segura, Inmaculada
    Li, Xiujuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Knevels, Ellen
    Costa, Sandra
    Vinckier, Stefan
    Dresselaer, Tom
    Åkerud, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    De Mol, Maria
    Salomäki, Henriikka
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Wyns, Sabine
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular and Morphological Pathology.
    Buysschaert, Ian
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular and Morphological Pathology.
    Himmelreich, Uwe
    Van Ginderachter, Jo A.
    De Palma, Michele
    Dewerchin, Mieke
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Carmeliet, Peter
    HRG Inhibits Tumor Growth and Metastasis by Inducing Macrophage Polarization and Vessel Normalization through Downregulation of PIGF2011In: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 19, no 1, p. 31-44Article in journal (Refereed)
    Abstract [en]

    Polarization of tumor-associated macrophages (TAMs) to a proangiogenic/immune-suppressive (M2-like) phenotype and abnormal, hypoperfused vessels are hallmarks of malignancy, but their molecular basis and interrelationship remains enigmatic. We report that the host-produced histidine-rich glycoprotein (HRG) inhibits tumor growth and metastasis, while improving chemotherapy. By skewing TAM polarization away from the M2- to a tumor-inhibiting M1-like phenotype, HRG promotes antitumor immune responses and vessel normalization, effects known to decrease tumor growth and metastasis and to enhance chemotherapy. Skewing of TAM polarization by HAG relies substantially on downregulation of placental growth factor (PIGF). Besides unveiling an important role for TAM polarization in tumor vessel abnormalization, and its regulation by HRG/PIGF, these findings offer therapeutic opportunities for anticancer and antiangiogenic treatment.

  • 199. Roxhed, Niclas
    et al.
    Samel, Björn
    Nordquist, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Griss, Patrick
    Stemme, Göran
    Painless drug delivery through microneedle-based transdermal patches featuring active infusion2008In: IEEE Transactions on Biomedical Engineering, ISSN 0018-9294, E-ISSN 1558-2531, Vol. 55, no 3, p. 1063-1071Article in journal (Refereed)
    Abstract [en]

    This paper presents the first microneedle-based transdermal patch with integrated active dispensing functionality. The electrically controlled system consists of a low-cost dosing and actuation unit capable of controlled release of liquid in the microliter range at low flow-rates and minimally invasive, side-opened, microneedles. The system was successfully tested in vivo by insulin administration to diabetic rats. Active infusion of insulin at 2 mul/h was compared to passive, diffusion-driven, delivery. Continuous active infusion caused significantly higher insulin concentrations in blood plasma. After a 3-h delivery period, the insulin concentration was five times larger compared to passive delivery. Consistent with insulin concentrations, actively administered insulin resulted in a significant decrease of blood glucose levels. Additionally, insertion and liquid injection was verified on human skin. This study shows the feasibility of a patch-like system with on-board liquid storage and dispensing capability. The proposed device represents a first step towards painless and convenient administration of macromolecular drugs such as insulin or vaccines.

  • 200.
    Rügheimer, Louise
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Wolgast, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Determination of the charge of the plasma proteins and consequent Donnan equilibrium across the capillary barriers in the rat microvasculature2008In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 194, no 4, p. 334-339Article in journal (Refereed)
    Abstract [en]

    Aim

    Due to the negatively charged proteins in plasma, a Donnan equilibrium will be formed between plasma and interstitium or, as in the glomerulus, between glomerular plasma and Bowman's space. The phenomenon is of great physiological significance in the sense that the electro-osmotic pressure offered by the small ions attracted to the proteins may account for an important part of the total colloid osmotic pressure and also as the electric potential consequent to the Donnan distribution will affect the transcapillary transport of all charged molecular compounds. The present study aimed at estimating the protein charge in rat plasma in order to validate its importance for colloid osmotic pressure and potential.

    Methods

    The charge of the plasma proteins was determined in vitro from the concentration of sodium across a cellophane membrane separating a rat plasma sample from saline alone. However, in order to improve the sensitivity of the method, the studies were carried out at an ionic strength of 1/10 of physiological saline.

    Results

    The average charge of plasma was estimated at 0.23 +/- 0.003 mEq g(-1) protein (mean +/- SE), and the standard variation at +/- 0.01 mEq g(-1), i.e. about 5%. At the normal protein concentration in Wistar rats of 50 g L-1, the charge of the proteins in systemic plasma was calculated to be 11.5 mEq L-1, whereas in glomerular and peritubular capillary plasma, the larger protein concentration increases the protein charge to 14.4 mEq L-1.

    Conclusion

    The results verify that the plasma protein charge accounts for about one-third of the total colloid osmotic pressure and that the obtained potential will constitute a major driving force for the transport of charged molecular compounds.

123456 151 - 200 of 258
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