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  • 101. Jädert, Cecilia
    et al.
    Petersson, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    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, Integrative Physiology.
    Grapensparr, Liza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Lundberg, Jon O.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Decreased leukocyte recruitment by inorganic nitrate and nitrite in microvascular inflammation and NSAID-induced intestinal injury2012In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 52, no 3, p. 683-692Article in journal (Refereed)
    Abstract [en]

    Nitric oxide (NO) generated by vascular NO synthases can exert anti-inflammatory effects, partly through its ability to decrease leukocyte recruitment. Inorganic nitrate and nitrite, from endogenous or dietary sources, have emerged as alternative substrates for NO formation in mammals. Bioactivation of nitrate is believed to require initial reduction to nitrite by oral commensal bacteria. Here we investigated the effects of inorganic nitrate and nitrite on leukocyte recruitment in microvascular inflammation and in NSAID-induced small-intestinal injury. We show that leukocyte emigration in response to the proinflammatory chemokine MIP-2 is reduced by 70% after 7 days of dietary nitrate supplementation as well as by acute intravenous nitrite administration. Nitrite also reduced leukocyte adhesion to a similar extent and this effect was inhibited by the soluble guanylyl cyclase inhibitor ODQ whereas the effect on emigrated leukocytes was not altered by this treatment. Further studies in INF-alpha-stimulated endothelial cells revealed that nitrite dose-dependently reduced the expression of ICAM-1. In rats and mice subjected to a challenge with diclofenac, dietary nitrate prevented the increase in myeloperoxidase and P-selectin levels in small-intestinal tissue. Antiseptic mouthwash, which eliminates oral nitrate reduction, markedly blunted the protective effect of dietary nitrate on P-selectin levels. Despite attenuation of the acute immune response, the overall ability to clear an infection with Staphylococcus aureus was not suppressed by dietary nitrate as revealed by noninvasive IVIS imaging. We conclude that dietary nitrate markedly reduces leukocyte recruitment to inflammation in a process involving attenuation of P-selectin and ICAM-1 upregulation. Bioactivation of dietary nitrate requires intermediate formation of nitrite by oral nitrate-reducing bacteria and then probably further reduction to NO and other bioactive nitrogen oxides in the tissues.

  • 102.
    Jönsson, Sofia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Becirovic Agic, Mediha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Narfström, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Melville, Jacqueline M
    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.
    Renal neurohormonal regulation in heart failure decompensation2014In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 307, no 5, p. 493-497Article in journal (Refereed)
    Abstract [en]

    Decompensation in heart failure occurs when the heart fails to balance venous return with cardiac output, leading to fluid congestion, and contributing to mortality. Decompensated heart failure can cause acute kidney injury (AKI), which further increases mortality. Heart failure activates signaling systems that are deleterious to kidneys such as renal sympathetic nerve activity (RSNA), renin-angiotensin-aldosterone system and vasopressin secretion. All three reduce renal blood flow (RBF) and increase tubular sodium reabsorption, which may increase renal oxygen consumption causing AKI through renal tissue hypoxia. Vasopressin contributes to venous congestion through aquaporin-mediated water retention. Additional water retention may be mediated through vasopressin-induced medullary urea transport and hyaluronan, but needs further study. In addition, there are several systems that could protect the kidneys and reduce fluid retention such as natriuretic peptides, prostaglandins and nitric oxide. However, the effect of natriuretic peptides and nitric oxide are blunted in decompensation, partly due to oxidative stress. This review considers how neurohormonal signaling in heart failure drives fluid retention by the kidneys and thus exacerbates decompensation. It further identifies areas where there is limited data, such as signaling systems 20-HETE, purines, endothelin, the role of renal water retention mechanisms for congestion and renal hypoxia in AKI during heart failure.

  • 103.
    Jönsson, Sofia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Melville, Jacqueline
    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.
    Norepinephrine effects are not affected by Losartan in rats after resuscitated haemorrhage2017In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 61, no 8, p. 963-963Article in journal (Other academic)
  • 104.
    Jönsson, Sofia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Melville, Jacqueline M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Agic, Mediha Becriovic
    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.
    Losartan does not decrease renal oxygenation and norepinephrine effects in rats after resuscitated hemorrhage.2018In: American Journal of Physiology - Renal Physiology, ISSN 1931-857X, E-ISSN 1522-1466, Vol. 315, no 2, p. F241-F246Article in journal (Refereed)
    Abstract [en]

    Renin-angiotensin-system blockers are thought to increase the risk of acute kidney injury after surgery and hemorrhage. We found that losartan does not cause renal cortical hypoxia after hemorrhage in rats because of decreased renal vascular resistance, but we did not evaluate resuscitation. We aimed to study losartan's effect on renal cortical and medullary oxygenation, as well as norepinephrine's vasopressor effect in a model of resuscitated hemorrhage. After 7 days of losartan (60 mg·kg-1·day-1) or control treatment, male Wistar rats were hemorrhaged 20% of their blood volume and resuscitated with Ringer's acetate. Mean arterial pressure, renal blood flow, and kidney tissue oxygenation were measured at baseline and after resuscitation. Finally, the effect of norepinephrine on mean arterial pressure and renal blood flow was investigated. As expected, losartan lowered mean arterial pressure but not renal blood flow. Losartan did not affect renal oxygen consumption and oxygen tension. Mean arterial pressure and renal blood flow were lower after resuscitated hemorrhage. A smaller increase of renal vascular resistance in the losartan group translated to a smaller decrease in cortical oxygen tension, but no significant difference was seen in medullary oxygen tension, either between groups or after hemorrhage. The effect of norepinephrine on mean arterial pressure and renal blood flow was similar in control- and losartan-treated rats. Losartan does not decrease renal oxygenation after resuscitated hemorrhage because of a smaller increase in renal vascular resistance. Further, losartan does not decrease the efficiency of norepinephrine as a vasopressor, indicating that blood pressure may be managed effectively during losartan treatment.

  • 105. Knapik, Piotr
    et al.
    Krzych, Łukasz J
    Weigl, Wojciech
    Adamski, Jan
    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.
    Mortality rate in Polish intensive care units is lower than predicted according to the APACHE II scoring system.2017In: Intensive Care Medicine, ISSN 0342-4642, E-ISSN 1432-1238, Vol. 43, p. 1745-1746Article in journal (Other academic)
  • 106.
    Kreuger, Johan
    et al.
    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.
    Targeting vascular and leukocyte communication in angiogenesis, inflammation and fibrosis2016In: Nature reviews. Drug discovery, ISSN 1474-1776, E-ISSN 1474-1784, Vol. 15, no 2, p. 125-142Article, review/survey (Refereed)
    Abstract [en]

    Regulation of vascular permeability, recruitment of leukocytes from blood to tissue and angiogenesis are all processes that occur at the level of the microvasculature during both physiological and pathological conditions. The interplay between microvascular cells and leukocytes during inflammation, together with the emerging roles of leukocytes in the modulation of the angiogenic process, make leukocyte-vascular interactions prime targets for therapeutics to potentially treat a wide range of diseases, including pathological and dysfunctional vessel growth, chronic inflammation and fibrosis. In this Review, we discuss how the different cell types that are present in and around microvessels interact, cooperate and instruct each other, and in this context we highlight drug targets as well as emerging druggable processes that can be exploited to restore tissue homeostasis.

  • 107.
    Källskog, Örjan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Autoregulation of Islet Graft Blood Flow Follows the Implantation2011In: Journal of Surgical Research, ISSN 0022-4804, E-ISSN 1095-8673, Vol. 171, no 2, p. 865-870Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Transplantation of pancreatic islets necessitates a revascularization, which is associated with a generalized graft vascular dysfunction, manifested, e.g., as a capillary hypertension, a decreased graft blood perfusion and graft hypoxia. Some of these changes can be due to impaired autoregulation of the newly formed vasculature in the islet grafts, and the aim of the present study was to further examine if this was the case.

    MATERIALS AND METHODS: We implanted 250 syngeneic islets under the renal capsule of rats and studied them 1 or 12-13 mo later. The blood perfusion of the whole kidney, renal cortex, and islet grafts were recorded in anesthetized animals with an ultrasound probe or laser-Doppler probes, respectively. The blood pressure in the kidneys was then gradually decreased by an adjustable clamp, during simultaneous measurement of blood flow values. RESULTS: The whole kidney, renal cortex, and islet grafts regulated their blood flow in concert with one another down to pressures of approximately 60 mmHg both 1 and 12-13 mo after implantation. However, the variability was greater at 1 mo.

    CONCLUSION: Islets transplanted under the renal capsule show similar autoregulatory properties with the kidney. It may be that the autoregulatory capacity of the renal interlobular arteries provides the underlying mechanism. This may be of importance for the good long-term survival of transplanted islets at this implantation site in experimental studies.

  • 108.
    Lai, En Yin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Patzak, Andreas
    Persson, A. Erik . G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Carlström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Angiotensin II enhances the afferent arteriolar response to adenosine through increases in cytosolic calcium2009In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 196, no 4, p. 435-445Article in journal (Refereed)
    Abstract [en]

     Aims: Angiotensin II (Ang II) is a strong renal vasoconstrictor and modulates the tubuloglomerular feedback (TGF). We hypothesized that Ang II at low concentrations enhances the vasoconstrictor effect of adenosine (Ado), the mediator of TGF. Methods: Afferent arterioles of mice were isolated and perfused, and both isotonic contractions and cytosolic calcium transients were measured. Results: Bolus application of Ang II (10(-12) and 10(-10)M) induced negligible vasoconstrictions, while Ang II at 10(-8) M reduced diameters by 35%. Ang II at 10(-12), 10(-10), and 10(-8) M clearly enhanced the arteriolar response to cumulative applications of Ado (10(-11) to 10(-4)M). Ado application increased the cytosolic calcium concentrations in the vascular smooth muscle, which were higher at 10(-5)M than at 10(-8)M. Ang II (10(-11) to 10(-6)M) also induced concentration-dependent calcium transients, which were attenuated by AT(1) receptor inhibition. Simultaneously applied Ang II (10(-10)M) additively enhanced the calcium transients induced by 10(-8) and 10(-5) M Ado. The transients were partly inhibited by AT(1) or A(1) receptor antagonists, but not significantly by A(2) receptor antagonists. Conclusion: A low dose of Ang II enhances Ado-induced constrictions, partly via AT(1) receptor-mediated calcium increase. Ado increases intracellular calcium by acting on A(1) but not A(2) receptors. The potentiating effect of Ang II on Ado-induced arteriolar vasoconstrictions may involve calcium sensitization of the contractile machinery, as Ang II only additively increased cytosolic calcium concentrations, while its effect on the arteriolar constriction was more than additive. The potentiating effect of Ang II might contribute to the resetting of TGF.

  • 109.
    Lai, En Yin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Patzak, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Steege, Andreas
    Mrowka, Ralf
    Brown, Russell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Spielmann, Nadine
    Persson, Pontus B.
    Fredholm, Bertil B.
    Persson, A. Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Contribution of adenosine receptors in the control of arteriolar tone and adenosine-angiotensin II interaction2006In: Kidney International, ISSN 0085-2538, E-ISSN 1523-1755, Vol. 70, no 4, p. 690-698Article in journal (Refereed)
    Abstract [en]

    Adenosine (Ado) mediates vasoconstriction via A(1)-Ado receptors and vasodilation via A(2)-Ado receptors in the kidney. It interacts with angiotensin II (Ang II), which is important for renal hemodynamics and tubuloglomerular feedback (TGF). The aim was to investigate the function of Ado receptors in the Ado -Ang II interaction in mouse microperfused, afferent arterioles. Ado (10(-11)-10(-4) mol/l) caused a biphasic response: arteriolar diameters were reduced (-7%) at Ado 10(-11)-10(-9) mol/l and returned to control values at higher concentrations. Treatment with Ang II (10(-10) mol/l) transformed the response into a concentration-dependent constriction. N-6-cyclopentyladenosine (A(1)-Ado receptor agonist) reduced diameters (12% at 10(-6) mol/l). Application of CGS21680 (10(-12)-10(-4) mol/l, A(2A) receptor agonist) increased the diameter by 13%. Pretreatment with ZM241385 (A(2A)-Ado receptor antagonist) alone or in combination with MRS1706 (A(2B)-Ado receptor antagonist) resulted in a pure constriction upon Ado, whereas 8-cyclopentyltheophylline (CPT) (A(1)-Ado receptor antagonist) inhibited the constrictor response. Afferent arterioles of mice lacking A(1)-Ado receptor did not show constriction upon Ado. Treatment with Ado (10(-8) mol/l) increased the response upon Ang II, which was blocked by CPT. Ado (10(-5) mol/l) did not influence the Ang II response, but an additional blockade of A(2)-Ado receptors enhanced it. The action of Ado on constrictor A(1)-Ado receptors and dilatory A(2)-Ado receptors modulates the interaction with Ang II. Both directions of Ado-Ang II interaction, which predominantly leads to an amplification of the contractile response, are important for the operation of the TGF.

  • 110.
    Lai, En Yin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Wang, Yibing
    Persson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Manning, Roy Davis, Jr.
    Liu, Ruisheng
    Pressure induces intracellular calcium changes in juxtaglomerular cells in perfused afferent arterioles2011In: Hypertension Research, ISSN 0916-9636, E-ISSN 1348-4214, Vol. 34, no 8, p. 942-948Article in journal (Refereed)
    Abstract [en]

    Calcium (Ca(2+)) has an important role in nearly all types of cellular secretion, with a particularly novel role in the juxtaglomerular (JG) cells in the kidney. In JG cells, Ca(2+) inhibits renin secretion, which is a major regulator of blood pressure and renal hemodynamics. However, whether alterations in afferent arteriolar (Af-Art) pressure change intracellular Ca(2+) concentration ([Ca(2+)](i)) in JG cells and whether [Ca(2+)](i) comes from extracellular or intracellular sources remains unknown. We hypothesize that increases in perfusion pressure in the Af-Art result in elevations in [Ca(2+)](i) in JG cells. We isolated and perfused Af-Art of C57BL6 mice and measured changes in [Ca(2+)](i) in JG cells in response to perfusion pressure changes. The JG cells' [Ca(2+)](i) was 93.3 +/- 2.2 nM at 60 mm Hg perfusion pressure and increased to 111.3 +/- 13.4, 119.6 +/- 7.3, 130.3 +/- 2.9 and 140.8 +/- 12.1 nM at 80, 100, 120 and 140 mm Hg, respectively. At 120 mm Hg, increases in [Ca(2+)](i) were reduced in mice receiving the following treatments: (1) the mechanosensitive cation channel blocker, gadolinium (94.6 +/- 7.5 nM); (2) L-type calcium channel blocker, nifedipine (105.8 +/- 7.5 nM); and (3) calcium-free solution plus ethylene glycol tetraacetic acid (96.0 +/- 5.8 nM). Meanwhile, the phospholipase C inhibitor, inositol triphosphate receptor inhibitor, T-type calcium channel blocker, N-type calcium channel blocker and Ca(2+)-ATPase inhibitor did not influence changes in [Ca(2+)](i) in JG cells. In summary, JG cell [Ca(2+)](i) rise as perfusion pressure increases; furthermore, the calcium comes from extracellular sources, specifically mechanosensitive cation channels and L-type calcium channels.

  • 111.
    Lau, Joey
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Svensson, J.
    Grapensparr, Liza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Johansson, Å
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Superior beta cell proliferation, function and gene expression in a subpopulation of rat islets identified by high blood perfusion2012In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 55, no 5, p. 1390-1399Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: The blood perfusion of individual pancreatic islets is highly variable, with a subgroup of islets having high perfusion and blood vessels responsive to further blood flow increase induced by glucose. This study tested the hypothesis that there is heterogeneity between islets with regard to beta cell proliferation, function and gene expression based on differences in their blood perfusion.

    Methods: Fluorescent microspheres were injected into the ascending aorta, and then microsphere-containing and non-microsphere-containing pancreatic islets were isolated for investigation. By this procedure, the 5% of islets with the greatest blood perfusion were identified for study. Islet endothelial cells were isolated separately to investigate the role of improved vascular support in the observed differences.

    Results: The vascular network was found to be more dense and tortuous in microsphere-containing than other islets. The most highly blood-perfused islets also had a higher rate of beta cell proliferation, superior beta cell function and a markedly different gene expression from other islets. Cultured islets exposed to islet endothelial cell products had a similarly increased beta cell proliferation rate, yet significantly fewer changes in gene expression than observed in the most highly blood-perfused islets.

    Conclusions/interpretation: A novel heterogeneity between islets was observed, with superior beta cell proliferation, function and gene expression in a subpopulation of islets identified by high blood perfusion. In contrast with a previously described population of low-oxygenated, sleeping islets, which are recruited into functionality when needed, the presently described heterogeneity is shown to remain in vitro after islet isolation.

  • 112. Laustsen, Christoffer
    et al.
    Nielsen, Per Mose
    Nørlinger, Thomas Stokholm
    Qi, Haiyun
    Pedersen, Uffe Kjærgaard
    Bertelsen, Lotte Bonde
    Østergaard, Jakob Appel
    Flyvbjerg, Allan
    Ardenkjær-Larsen, Jan Henrik
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Stødkilde-Jørgensen, Hans
    Antioxidant treatment attenuates lactate production in diabetic nephropathy2017In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 312, no 1, p. F192-F199Article in journal (Refereed)
    Abstract [en]

    The early progression of diabetic nephropathy is notoriously difficult to detect and quantify before the occurrence of substantial histological damage. Recently, hyperpolarized [1-(13)C]pyruvate has demonstrated increased lactate production in the kidney early after the onset of diabetes, implying increased lactate dehydrogenase activity as a consequence of increased nicotinamide adenine dinucleotide substrate availability due to upregulation of the polyol pathway, i.e., pseudohypoxia. In this study, we investigated the role of oxidative stress in mediating these metabolic alterations using state-of-the-art hyperpolarized magnetic resonance (MR) imaging. Ten-week-old female Wistar rats were randomly divided into three groups: healthy controls, untreated diabetic (streptozotocin treatment to induce insulinopenic diabetes), and diabetic, receiving chronic antioxidant treatment with TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl) via the drinking water. Examinations were performed 2, 3, and 4 wk after the induction of diabetes by using a 3T Clinical MR system equipped with a dual tuned (13)C/(1)H-volume rat coil. The rats received intravenous hyperpolarized [1-(13)C]pyruvate and were imaged using a slice-selective (13)C-IDEAL spiral sequence. Untreated diabetic rats showed increased renal lactate production compared with that shown by the controls. However, chronic TEMPOL treatment significantly attenuated diabetes-induced lactate production. No significant effects of diabetes or TEMPOL were observed on [(13)C]alanine levels, indicating an intact glucose-alanine cycle, or [(13)C]bicarbonate, indicating normal flux through the Krebs cycle. In conclusion, this study demonstrates that diabetes-induced pseudohypoxia, as indicated by an increased lactate-to-pyruvate ratio, is significantly attenuated by antioxidant treatment. This demonstrates a pivotal role of oxidative stress in renal metabolic alterations occurring in early diabetes.

  • 113.
    Lefranc, Clara
    et al.
    Paris Descartes Univ, Pierre & Marie Curie Univ, INSERM, Ctr Rech Cordeliers, UMRS 1138, Paris, France.
    Friederich, Malou
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Palacios-Ramirez, Roberto
    Paris Descartes Univ, Pierre & Marie Curie Univ, INSERM, Ctr Rech Cordeliers,UMRS 1138, Paris, France.
    Cat, Aurelie Nguyen Dinh
    Paris Descartes Univ, Pierre & Marie Curie Univ, INSERM, Ctr Rech Cordeliers,UMRS 1138, Paris, France.
    Mitochondrial oxidative stress in obesity: role of the mineralocorticoid receptor2018In: Journal of Endocrinology, ISSN 0022-0795, E-ISSN 1479-6805, Vol. 238, no 3, p. R143-R159Article, review/survey (Refereed)
    Abstract [en]

    Obesity is a multifaceted, chronic, low-grade inflammation disease characterized by excess accumulation of dysfunctional adipose tissue. It is often associated with the development of cardiovascular (CV) disorders, insulin resistance and diabetes. Under pathological conditions like in obesity, adipose tissue secretes bioactive molecules called 'adipokines', including cytokines, hormones and reactive oxygen species (ROS). There is evidence suggesting that oxidative stress, in particular, the ROS imbalance in adipose tissue, may be the mechanistic link between obesity and its associated CV and metabolic complications. Mitochondria in adipose tissue are an important source of ROS and their dysfunction contributes to the pathogenesis of obesity-related type 2 diabetes. Mitochondrial function is regulated by several factors in order to preserve mitochondria integrity and dynamics. Moreover, the renin-angiotensin-aldosterone system is over-activated in obesity. In this review, we focus on the pathophysiological role of the mineralocorticoid receptor in the adipose tissue and its contribution to obesity-associated metabolic and CV complications. More specifically, we discuss whether dysregulation of the mineralocorticoid system within the adipose tissue may be the upstream mechanism and one of the early events in the development of obesity, via induction of oxidative stress and mitochondrial dysfunction, thus impacting on systemic metabolism and the CV system.

  • 114. Leh, Sabine
    et al.
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Rosenberger, Christian
    Iversen, Bjarne M.
    Afferent arteriolopathy and glomerular collapse but not segmental sclerosis induce tubular atrophy in old spontaneously hypertensive rats2011In: Virchows Archiv, ISSN 0945-6317, E-ISSN 1432-2307, Vol. 459, no 1, p. 99-108Article in journal (Refereed)
    Abstract [en]

    In chronic renal disease, the temporal and spatial relationship between vascular, glomerular and tubular changes is still unclear. Hypertension, an important cause of chronic renal failure, leads to afferent arteriolopathy, segmental glomerulosclerosis and tubular atrophy in the juxtamedullary cortex. We investigated the pathological changes of hypertensive renal disease in aged spontaneously hypertensive rats using a large number of serial sections, where we traced and analyzed afferent arteriole, glomerulus and proximal tubule of single nephrons. Our major finding was that both afferent arteriolopathy and glomerular capillary collapse were linked to tubular atrophy. Only nephrons with glomerular collapse (n = 13) showed tubules with reduced diameter indicating atrophy [21.66 +/- 2.56 mu m vs. tubules in normotensive Wistar Kyoto rats (WKY) 38.56 +/- 0.56 mu m, p < 0.05], as well as afferent arteriolar wall hypertrophy (diameter 32.74 +/- 4.72 mu m vs. afferent arterioles in WKY 19.24 +/- 0.98 mu m, p < 0.05). Nephrons with segmental sclerosis (n = 10) did not show tubular atrophy and tubular diameters were unchanged (35.60 +/- 1.43 mu m). Afferent arteriolar diameter negatively correlated with glomerular capillary volume fraction (r = -0.36) and proximal tubular diameter (r = -0.46) implying reduced glomerular and tubular flow. In line with this, chronically damaged tubules showed reduced staining for the ciliary protein inversin indicating changed ciliary signalling due to reduced urinary flow. This is the first morphological study on hypertensive renal disease making correlations between vascular, glomerular and tubular components of individual nephron units. Our data suggest that afferent arteriolopathy leads to glomerular collapse and reduced urinary flow with subsequent tubular atrophy.

  • 115.
    Liljebäck, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Grapensparr, Liza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Olerud, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Carlsson, Per-Ola
    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 Sciences, Transplantation and regenerative medicine.
    Extensive Loss of Islet Mass Beyond the First Day After Intraportal Human Islet Transplantation in a Mouse Model2016In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 25, no 3, p. 481-489Article in journal (Refereed)
    Abstract [en]

    Clinical islet transplantation is characterized by a progressive deterioration of islet graft function, which renders many patients once again dependent on exogenous insulin administration within a couple of years. In this study, we aimed to investigate possible engraftment factors limiting the survival and viability of experimentally transplanted human islets beyond the first day after their transplantation to the liver. Human islets were transplanted into the liver of nude mice and characterized 1 or 30 days after transplantation by immunohistochemistry. The factors assessed were endocrine mass, cellular death, hypoxia, vascular density and amyloid formation in the transplanted islets. One day posttransplantation, necrotic cells, as well as apoptotic cells, were commonly observed. In contrast to necrotic death, apoptosis rates remained high 1 month posttransplantation, and the total islet mass was reduced by more than 50% between 1 and 30 days posttransplantation. Islet mass at 30 days posttransplantation correlated negatively to apoptotic death. Vascular density within the transplanted islets remained less than 30% of that in native human islets up to 30 days posttransplantation and was associated with prevailing hypoxia. Amyloid formation was rarely observed in the 1-day-old transplants, but was commonly observed in the 30-day-old islet transplants. We conclude that substantial islet cell death occurs beyond the immediate posttransplantation phase, particularly through apoptotic events. Concomitant low vascularization with prevailing hypoxia and progressive amyloid development was observed in the human islet grafts. Strategies to improve engraftment at the intraportal site or change of implantation site in the clinical setting are needed.

  • 116. Lindahl, Emma
    et al.
    Nordquist, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Müller, Patrick
    El Agha, Eli
    Friederich, Malou
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Dahlman-Wright, Karin
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Jörnvall, Hans
    Early transcriptional regulation by C-peptide in freshly isolated rat proximal tubular cells2011In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 27, no 7, p. 697-704Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Clinical studies have shown that proinsulin C-peptide exerts renoprotective effects in type 1 diabetes, although the underlying mechanisms are poorly understood. As C-peptide has been shown to induce several intracellular events and to localize to nuclei, we aimed to determine whether gene transcription is affected in proximal tubular kidney cells, and if so, whether genes with altered transcription include those related to protective mechanisms. METHODS: The effect of C-peptide incubation (2h) on gene expression was investigated in freshly isolated proximal tubular cells from streptozotocin-diabetic Sprague-Dawley rats using global gene expression profiling and RT-qPCR. Protein expression was assayed using western blotting. Different bioinformatic strategies were employed. RESULTS: Gene transcription profiling demonstrated differential transcription of 492 genes (p<0.01) after 2h of C-peptide exposure, with the majority of these genes repressed (83%). RT-qPCR validation supported a trend of several GPCR's being activated, and certain transcription factors to be repressed. Also, C-peptide repressed the transcription of genes associated with pathways of circulatory and inflammatory diseases. CONCLUSIONS: This study shows that C-peptide exerts early effects on gene transcription in proximal tubular cells. The findings also bring further knowledge to the renoprotective mechanisms of C-peptide in type I diabetes, and supports a transcriptional activity for C-peptide. It is suggested that C-peptide may play a regulatory role in the gene expression of proximal tubular cells.

  • 117.
    Liss, Per
    et al.
    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, Integrative Physiology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    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.
    Iodinated contrast media decrease renomedullary blood flow. A possible cause of contrast media-induced nephropathy2009In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 645, p. 213-218Article in journal (Refereed)
    Abstract [en]

    The renal medulla has been implicated as a key target for contrast media-induced nephropathy (CIN). Although the effects of contrast media (CM) on whole kidney blood flow are well characterized, the effect of CM on renal medullary blood flow has been controversial. It has been reported that an extremely high dose of a high osmolar CM (iothalamate; 2900 mg I/kg bw) injected rapidly increased the renal outer medullary blood flow (OMBF). However, more clinical relevant doses consistently result in a sustained decrease in medullary blood flow. Furthermore, simultaneous measurements using both laser-Doppler flowmetry and hydrogen washout yield similar results of a decrease in OMBF after CM administration. CM induced a transient 28% decrease in the laser-Doppler signal from the outer medulla, while the hydrogen washout rate in the same region was reduced by approximately 50%. Furthermore, CM administration consistently results in decreased medullary oxygen tension (PO2). The renal medulla works already during normal physiological conditions at the verge of hypoxia, and the majority of the studies published so far are in agreement with the hypothesis that CIN may have its origin in a further reduction in blood flow and/or oxygen availability of this region of the kidney.

  • 118.
    Liss, Per
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Hansell, Peter
    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.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Iodinated contrast media inhibit oxygen consumption in freshly isolated proximal tubular cells from elderly humans and diabetic rats: Influence of nitric oxide.2016In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 121, no 1, p. 12-16Article in journal (Refereed)
    Abstract [en]

    Objectives Mechanisms underlying contrast medium (CM)-induced nephropathy remain elusive, but recent attention has been directed to oxygen availability. The purpose of this study was to evaluate the effect of the low-osmolar CM iopromide and the iso-osmolar CM iodixanol on oxygen consumption (QO2) in freshly isolated proximal tubular cells (PTC) from kidneys ablated from elderly humans undergoing nephrectomy for renal carcinomas and from normoglycemic or streptozotocin-diabetic rats. Materials PTC were isolated from human kidneys, or kidneys of normoglycemic or streptozotocin-diabetic rats. QO2 was measured with Clark-type microelectrodes in a gas-tight chamber with and without each CM (10 mg I/mL medium). L-NAME was used to inhibit nitric oxide (NO) production caused by nitric oxide synthase. Results Both CM reduced QO2 in human PTC (about -35%) which was prevented by L-NAME. PTC from normoglycemic rats were unaffected by iopromide, whereas iodixanol decreased QO2 (-34%). Both CM decreased QO2 in PTC from diabetic rats (-38% and -36%, respectively). L-NAME only prevented the effect of iopromide in the diabetic rat PTC. Conclusions These observations demonstrate that CM can induce NO release from isolated PTC in vitro, which affects QO2. Our results suggest that the induction of NO release and subsequent effect on the cellular oxygen metabolism are dependent on several factors, including CM type and pre-existing risk factors for the development of CM-induced nephropathy.

  • 119.
    Liss, Per
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Hansell, Peter
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Palm, Fredrik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Lagerqvist, Bo
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Är de nya iso-osmolära röntgenkontrastmedlen mindre njurskadliga jämfört med de låg-osmolära?2007In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 104, no 20-21, p. 1577-Article, review/survey (Other academic)
  • 120.
    Liu, Haoyu
    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.
    Cai, Demin
    Univ Calif Davis, Dept Biochem & Mol Med, Sacramento, CA 95817 USA.
    Ahl, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Bertilsson, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Nyman, Margareta
    Lund Univ, Dept Food Technol Engn & Nutr, S-22100 Lund, Sweden.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Dietary Fiber in Bilberry Ameliorates Pre-Obesity Events in Rats by Regulating Lipid Depot, Cecal Short-Chain Fatty Acid Formation and Microbiota Composition2019In: Nutrients, ISSN 2072-6643, E-ISSN 2072-6643, Vol. 11, no 6, article id 1350Article in journal (Refereed)
    Abstract [en]

    Obesity is linked to non-alcoholic fatty liver disease and risk factors associated to metabolic syndrome. Bilberry (Vaccinium myrtillus) that contains easily fermentable fiber may strengthen the intestinal barrier function, attenuate inflammation and modulate gut microbiota composition, thereby prevent obesity development. In the current study, liver lipid metabolism, fat depot, cecal and serum short-chain fatty acids (SCFAs) and gut microbiome were evaluated in rats fed bilberries in a high-fat (HFD + BB) or low-fat (LFD + BB) setting for 8 weeks and compared with diets containing equal amount of fiber resistant to fermentation (cellulose, HFD and LFD). HFD fed rats did not obtain an obese phenotype but underwent pre-obesity events including increased liver index, lipid accumulation and increased serum cholesterol levels. This was linked to shifts of cecal bacterial community and reduction of major SCFAs. Bilberry inclusion improved liver metabolism and serum lipid levels. Bilberry inclusion under either LFD or HFD, maintained microbiota homeostasis, stimulated interscapular-brown adipose tissue depot associated with increased mRNA expression of uncoupling protein-1; enhanced SCFAs in the cecum and circulation; and promoted butyric acid and butyrate-producing bacteria. These findings suggest that bilberry may serve as a preventative dietary measure to optimize microbiome and associated lipid metabolism during or prior to HFD.

  • 121.
    Lofton Tomenius, Hava
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Vågesjö, Evelina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Öhnstedt, E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Mortier, A.
    Katholieke Univ Leuven, Leuven, Belgium.
    Roos, S.
    Swedish Univ Agr Sci, Uppsala, Sweden.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    A novel drug-delivery system and drug candidate: using probiotic bacteria as bioreactors for delivery of therapeutic chemokines in wound healing2018In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 48, no S1, p. 79-79Article in journal (Other academic)
  • 122.
    Lomei, Jalal
    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, Integrative Physiology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Pro-angiogenic neutrophils are potentiated by hypoxiaManuscript (preprint) (Other academic)
    Abstract [en]

    Abstract

    Hypoxia, shortage of oxygen in tissues, is closely related to injury, inflammation and tissue damage. One way to overcome this issue is increasing angiogenesis, growing new blood vessels from preexist-ing ones, at the site of hypoxia. Considerable number of cells, factors and signaling pathways are involved in regulating angiogenesis.

    Neutrophils have been detected at the site of hypoxia and it has been shown that a subpopulation of these cells, pro-angiogenic neutrophils, PANs is actively involved in increasing angiogenesis. In this study, the effect of hypoxia on PANs was studied by co-culturing PANs with growing endothelial cells using in vitro angiogenesis assay and hypoxic and normoxic incubator. Moreover, life spans of neutrophils and PANs, as well as expression of PANs specific markers have been investigated under hypoxia and normoxia.  

    Our data shows that the ability of PANs, to induce angiogenesis was increased under hypoxic conditions. Moreover larger number of PANs survived while co-culturing with active growing endothelial cells. We thereby conclude that the hypoxic microenvironment primes pro-angiogenic neutrophils increase their pro-angiogenic ability.

  • 123.
    Lomei, Jalal
    et al.
    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.
    Giraud, Antoine
    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 Medical Biochemistry and Microbiology.
    Herrera Hidalgo, Carmen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Shibuya, Masabumi
    Jobu University, Gunma, Japan..
    Christoffersson, Gustaf
    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.
    Characterization of pro-angiogenic neutrophilsManuscript (preprint) (Other academic)
    Abstract [en]

    The roles of neutrophils in immune defense have been investigated for decades. These cells are well equipped to protect the body in several ways against invaders such as microorganism. Recently it has been reported that neutrophils also contribute to angiogenesis; they are recruited to the site of hypoxia where they can promote blood vessel formation, as demonstrated both in vivo and in vitro. We found that these neutrophils with proangiogenic actions form a specific subset of the circulating neutrophils. The proangiogenic neutrophils (PANs) exclusively express the adhesion molecule CD49d and vascular endothelial growth factor receptor 1 (VEGFR1), and contribute to angiogenesis by delivering MMP-9 (matrix metalloproteinase 9). In this study, PANs were compared to classic neutrophils in respect to physical features as well as functionality. We found that PANs in humans were smaller and in human and mice PANs had higher granularity compared to the classic neutrophils. Moreover, they were more efficient phagocytes than classic neutrophils. In the aortic ring model of angiogenesis, vessel neo-formation was increased by the presence of pro-angiogenic neutrophils. Finally, by using neutrophils from mice with impaired VEGFR1 receptor (Flt-1 tk-/- mice) we demonstrated the role of VEGFR1 in neutrophil recruitment towards angiogenic endothelium. Together these results show clear differences between the pro-angiogenic subpopulation and the classic neutrophils, which further solidify the conclusion of a specific neutrophil subpopulation.

  • 124. Lundberg, Jon O.
    et al.
    Carlström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Larsen, Filip J.
    Weitzberg, Eddie
    Roles of dietary inorganic nitrate in cardiovascular health and disease2011In: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, Vol. 89, no 3, p. 525-532Article, review/survey (Refereed)
    Abstract [en]

    Inorganic nitrate from dietary and endogenous sources is emerging as a substrate for in vivo generation of nitric oxide (NO) and other reactive nitrogen oxides. Dietary amounts of nitrate clearly have robust NO-like effects in humans, including blood pressure reduction, inhibition of platelet aggregation, and vasoprotective activity. In animal models, nitrate protects against ischaemia-reperfusion injuries and several other types of cardiovascular disorders. In addition, nitrate most surprisingly decreases whole body oxygen cost during exercise with preserved or even enhanced maximal performance. Oxidative stress and reduced NO bioavailability are critically linked to development of hypertension and other forms of cardiovascular diseases. Mechanistically, a central target for the effects of nitrate and its reaction products seems to be the mitochondrion and modulation of oxidative stress. All in vivo effects of nitrate are achievable with amounts corresponding to a rich intake of vegetables, which are particularly rich in this anion. A theory is now emerging suggesting nitrate as an active component in vegetables contributing to the beneficial health effects of this food group, including protection against cardiovascular disease and type-2 diabetes.

  • 125.
    Malinovschi, Andrei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Nordvall, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Basal and induced NO formation in the pharyngo-oral tract influences estimates of alveolar NO levels2009In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 106, no 2, p. 513-519Article in journal (Refereed)
    Abstract [en]

    The present study analyzed how models currently used to distinguish alveolar from bronchial contribution to exhaled nitric oxide (NO) are affected by manipulation of NO formation in the pharyngo-oral tract. Exhaled NO was measured at multiple flow rates in 15 healthy subjects in two experiments: 1) measurements at baseline and 5 min after chlorhexidine (CHX) mouthwash and 2) measurements at baseline, 60 min after ingestion of 10 mg NaNO3/kg body wt, and 5 min after CHX mouthwash. Alveolar NO concentration (CalvNO) and bronchial flux (J′awNO) were calculated by using the slope-intercept model with or without adjustment for trumpet shape of airways and axial diffusion (TMAD). Salivary nitrate and nitrite were measured in the second experiment. CalvNO [median (range)] was reduced from 1.16 ppb (0.77, 1.96) at baseline to 0.84 ppb (0.57, 1.48) 5 min after CHX mouthwash (P < 0.001). The TMAD-adjusted CalvNO value after CHX mouthwash was 0.50 ppb (0, 0.85). The nitrate load increased J′awNO from 32.2 nl/min (12.2, 60.3) to 57.1 nl/min (22.0, 119) in all subjects and CalvNO from 1.47 ppb (0.73, 1.95) to 1.87 ppb (10.85, 7.20) in subjects with high nitrate turnover (>10-fold increase of salivary nitrite after nitrate load). CHX mouthwash reduced CalvNO levels to 1.15 ppb (0.72, 2.07) in these subjects with high nitrate turnover. All these results remained consistent after TMAD adjustment. We conclude that estimated alveolar NO concentration is affected by pharyngo-oral tract production of NO in healthy subjects, with a decrease after CHX mouthwash. Moreover, unknown ingestion of dietary nitrate could significantly increase estimated alveolar NO in subjects with high nitrate turnover, and this might be falsely interpreted as a sign of peripheral inflammation. These findings were robust for TMAD.

  • 126.
    Malinovschi, Andrei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Holmkvist, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Norbäck, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Meriläinen, P.
    Högman, Marieann
    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, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Effect of smoking on exhaled nitric oxide and flow-independent nitric oxide exchange parameters2006In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 28, no 2, p. 339-345Article in journal (Refereed)
    Abstract [en]

    It is a well-known fact that smoking is associated with a reduction in exhaled nitric oxide (NO) levels. There is, however, limited knowledge relating to the smoking-induced changes in production or exchange of NO in different compartments of the airways. This study comprised 221 adult subjects from the European Community Respiratory Health Survey 11, who were investigated in terms of their exhaled NO, lung function, immunoglobulin E sensitisation and smoking habits. The following parameters were determined using extended NO analysis: airway tissue nitric oxide concentration (Caw,NO), airway transfer factor (or diffusing capacity) for nitric oxide (Daw,NO), alveolar nitric oxide concentration (CA,No) and fractional exhaled nitric oxide concentration at a flow rate of 50 mL(.)s(-1) (FeNO,0.05). Maximum total airway nitric oxide flux (J'aw,NO) was calculated from Daw,NO(Caw,NO-CA,NO). Current smokers (n=35) exhibited lower (geometric mean) FeNO,0.05 (14.0 versus 22.8 ppb), Caw,NO (79.0 versus 126 ppb) and J'aw,NO (688 versus 1,153 pL(.)s(-1)) than never-smokers (n=111). Ex-smokers (n=75) were characterised by lower FeNO,0.05 (17.7 versus 22.8 ppb) and Jaw,NO (858 versus 1,153 pL-s(-1)) than never-smokers. These relationships were maintained after adjusting for potential confounders (sex, age, height, immunoglobulin E sensitisation and forced expiratory volume in one second), and, in this analysis, a negative association was found between current smoking and CA,NO. Snus (oral moist snuff) consumption (n=21) in ex-smokers was associated with an increase in Daw,NO and a reduction in Caw,No, after adjusting for potential confounders. Passive smoking was associated with a higher CA,NO. Using extended nitric oxide analysis, it was possible to attribute the reduction in exhaled nitric oxide levels seen in ex- and current smokers to 6 lower total airway nitric oxide flux in ex-smokers and reduced airway and alveolar nitric oxide concentrations in current smokers. The association between snus (oral tobacco) use and reduced nitric oxide concentrations in the airways and increased nitric oxide transfer from the airways warrants further studies.

  • 127.
    Malinovschi, Andrei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Holmkvist, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Norbäck, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Meriläinen, Pekka
    Högman, Marieann
    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, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    IgE sensitisation in relation to flow-independent nitric oxide exchange parameters2006In: Respiratory research (Online), ISSN 1465-9921, E-ISSN 1465-993X, Vol. 7, p. 92-Article in journal (Refereed)
    Abstract [en]

    Background: A positive association between IgE sensitisation and exhaled NO levels has been found in several studies, but there are no reports on the compartment of the lung that is responsible for the increase in exhaled NO levels seen in IgE-sensitised subjects.

    Methods: The present study comprised 288 adult subjects from the European Community Respiratory Health Survey II who were investigated in terms of lung function, IgE sensitisation ( sum of specific IgE), smoking history and presence of rhinitis and asthma. Mean airway tissue concentration of NO (Caw(NO)), airway transfer factor for NO (Daw(NO)), mean alveolar concentration of NO (Calv(NO)) and fractional exhaled concentration of NO at a flow rate of 50 mL s(-1) ( FENO0.05) were determined using the extended NO analysis.

    Results: IgE-sensitised subjects had higher levels ( geometric mean) of FENO 0.05 (24.9 vs. 17.3 ppb) ( p < 0.001), Daw(NO) ( 10.5 vs. 8 mL s(-1)) ( p = 0.02) and Caw(NO) (124 vs. 107 ppb) ( p < 0.001) and positive correlations were found between the sum of specific IgE and FENO 0.05, Caw(NO) and Daw(NO) levels ( p < 0.001 for all correlations). Sensitisation to cat allergen was the major determinant of exhaled NO when adjusting for type of sensitisation. Rhinitis and asthma were not associated with the increase in exhaled NO variables after adjusting for the degree of IgE sensitisation.

    Conclusion: The presence of IgE sensitisation and the degree of allergic sensitisation were related to the increase in airway NO transfer factor and the increase in NO concentration in the airway wall. Sensitisation to cat allergen was related to the highest increases in exhaled NO parameters. Our data suggest that exhaled NO is more a specific marker of allergic inflammation than a marker of asthma or rhinitis.

  • 128. Martinka, P
    et al.
    Lai, E Y
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Fähling, M
    Jankowski, V
    Jankowski, J
    Schubert, R
    Gaestel, M
    Persson, A E G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Persson, P B
    Patzak, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Adenosine increases calcium sensitivity via receptor-independent activation of the p38/MK2 pathway in mesenteric arteries2008In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 193, no 1, p. 37-46Article in journal (Refereed)
    Abstract [en]

    AIM: Adenosine (Ado) restores desensitized angiotensin II-induced contractions in the renal arterioles via an intracellular, receptor-independent mechanisms including the p38 mitogen-activated protein kinase (MAPK). In the present study we test the hypothesis that MAPK-activated protein kinase 2 (MK2) mediates the Ado effect downstream from p38 MAPK resulting in an increased phosphorylation of the regulatory unit of the myosin light chain (MLC(20)). METHODS AND RESULTS: Contraction experiments were performed in rings of mesenteric arteries under isometric conditions in C57BL6 and MK2 knock out mice (MK2-/-). Ado pretreatment (10(-5) mol L(-1)) strongly increased Ang II sensitivity, calcium sensitivity and the phosphorylation of MLC(20). Treatment with Ado (3 x 10(-6) or 10(-5) mol L(-1) in between successive Ang II applications) enhanced the desensitized Ang II responses (second to fifth application). Ca(2+) transients were not effected by Ado. Further, blockade of type 1 and type 2 Ado receptors during treatment did not influence the effect. Type 3 receptor activation by inosine instead of Ado had no effect. Conversely, inhibition of nitrobenzylthioinosine-sensitive Ado transporters prevented the effects of Ado. Inhibition of p38 MAPK as well as use of MK2-/- mice prevented contractile Ado effects on the mesenteric arteries and the phosphorylation of MLC(20). CONCLUSION: The study shows that Ado activates the p38 MAPK/MK2 pathway in vascular smooth muscle via an intracellular action, which results in an increased MLC(20) phosphorylation in concert with increased calcium sensitivity of the contractile apparatus. This mechanism can significantly contribute to the regulation of vascular tone, e.g. under post-ischaemic conditions.

  • 129.
    Massena, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    A close-up on neutrophils: Visualizing the mechanisms of their in vivo recruitment and function2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    A successful immune response depends on prompt and sufficient recruitment of leukocytes from the circulation to infected or injured sites. Mobilization of leukocytes to hypoxic tissues is vital for angiogenesis, i.e. the formation of new blood vessels from preexisting vasculature, and thus crucial for tissue growth and regeneration. Deviations from normal leukocyte recruitment drive a variety of pathologies, including chronic inflammation, autoimmune diseases and cancer, for which therapeutic options are limited or unspecific. Understanding the mechanisms by which the body controls leukocyte recruitment is therefore critical for the development of novel therapeutic strategies.

    The present investigations focused on delineating the mechanisms behind leukocyte mobilization from the bloodstream to afflicted sites, by means of in vivo imaging techniques and in vitro assays. We demonstrate that, in response to inflammation, increased vascular permeability enhances transendothelial transport of tissue-released chemokines. Within the vasculature, chemokines form a chemotactic gradient sequestered on heparan sulfate, which directs crawling neutrophils and expedites their extravasation to the inflamed tissue. Consequently, gradient formation grants efficient bacterial clearance. Citrullination of chemokines by leukocyte-derived PAD enzymes in the inflamed tissue prevents chemokine transport into blood vessels, which dampens further neutrophil recruitment and thereby controls the amplitude of the inflammatory response. Moreover, the mechanisms of neutrophil recruitment in response to proangiogenic factors released during hypoxia are revealed to differ from those observed during classical inflammation. Particularly, VLA-4 integrin and VEGFR1 expressed on a defined subset of neutrophils, along with endothelial VEGFR2, are required for efficient neutrophil recruitment to hypoxia. Rather than stimulus-induced phenotypic changes on neutrophils, specific neutrophil subtypes with innate proinflammatory or proangiogenic functions (respectively, CD49d-VEGFR1lowCXCR4low and CD49d+VEGFR1highCXCR4high) coexist in the circulation of humans and mice.

    In summary, this dissertation provides relevant information on specific steps of neutrophil recruitment to inflamed or hypoxic tissues, which may represent future means to down-regulate aberrant immune responses during chronic inflammation and autoimmune diseases; to increase angiogenesis during ischemia; or to limit pathological angiogenesis, a characteristic of tumor growth and of several chronic inflammatory disorders.

    List of papers
    1. A chemotactic gradient sequestered on endothelial heparan sulfate induces directional intraluminal crawling of neutrophils
    Open this publication in new window or tab >>A chemotactic gradient sequestered on endothelial heparan sulfate induces directional intraluminal crawling of neutrophils
    Show others...
    2010 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 116, no 11, p. 1924-1931Article in journal (Refereed) Published
    Abstract [en]

    During infection, chemokines sequestered on endothelium induce recruitment of circulating leukocytes into the tissue where they chemotax along chemokine gradients toward the afflicted site. The aim of this in vivo study was to determine whether a chemokine gradient was formed intravascularly and influenced intraluminal neutrophil crawling and transmigration. A chemokine gradient was induced by placing a macrophage inflammatory protein-2 (MIP-2)-containing (CXCL2) gel on the cremaster muscle of anesthetized wild-type mice or heparanase-overexpressing transgenic mice (hpa-tg) with truncated heparan sulfate (HS) side chains. Neutrophil-endothelial interactions were visualized by intravital microscopy and chemokine gradients detected by confocal microscopy. Localized extravascular chemokine release (MIP-2 gel) induced directed neutrophil crawling along a chemotactic gradient immobilized on the endothelium and accelerated their recruitment into the target tissue compared with homogeneous extravascular chemokine concentration (MIP-2 super-fusion). Endothelial chemokine sequestration occurred exclusively in venules and was HS-dependent, and neutrophils in hpa-tg mice exhibited random crawling. Despite similar numbers of adherent neutrophils in hpa-tg and wild-type mice, the altered crawling in hpa-tg mice was translated into decreased number of emigrated neutrophils and ultimately decreased the ability to clear bacterial infections. In conclusion, an intravascular chemokine gradient sequestered by endothelial HS effectively directs crawling leukocytes toward transmigration loci close to the infection site.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-134806 (URN)10.1182/blood-2010-01-266072 (DOI)000282152000018 ()20530797 (PubMedID)
    Available from: 2010-12-01 Created: 2010-12-01 Last updated: 2017-12-12Bibliographically approved
    2. Increased vascular permeability facilitates vascular influx of chemokines and accelerates recruitment of circulating neutrophils
    Open this publication in new window or tab >>Increased vascular permeability facilitates vascular influx of chemokines and accelerates recruitment of circulating neutrophils
    (English)Manuscript (preprint) (Other academic)
    National Category
    Physiology
    Identifiers
    urn:nbn:se:uu:diva-265202 (URN)
    Available from: 2015-11-01 Created: 2015-10-25 Last updated: 2018-01-10
    3. Identification and characterization of VEGF-A-responsive neutrophils expressing CD49d, VEGFR1, and CXCR4 in mice and humans
    Open this publication in new window or tab >>Identification and characterization of VEGF-A-responsive neutrophils expressing CD49d, VEGFR1, and CXCR4 in mice and humans
    Show others...
    2015 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 17, p. 2016-2026Article in journal (Refereed) Published
    Abstract [en]

    Vascular endothelial growth factor A (VEGF-A) is upregulated during hypoxia and is the major regulator of angiogenesis. VEGF-A expression has also been found to recruit myeloid cells to ischemic tissues where they contribute to angiogenesis. This study investigates the mechanisms underlying neutrophil recruitment to VEGF-A as well as the characteristics of these neutrophils. A previously undefined circulating subset of neutrophils shown to be CD49d(+)VEGFR1(high)CXCR4(high) was identified in mice and humans. By using chimeric mice with impaired VEGF receptor 1 (VEGFR1) or VEGFR2 signaling (Flt-1tk(-/-), tsad(-/-)), we found that parallel activation of VEGFR1 on neutrophils and VEGFR2 on endothelial cells was required for VEGF-A-induced recruitment of circulating neutrophils to tissue. Intravital microscopy of mouse microcirculation revealed that neutrophil recruitment by VEGF-A versus by the chemokine macrophage inflammatory protein 2 (MIP-2 [CXCL2]) involved the same steps of the recruitment cascade but that an additional neutrophil integrin (eg, VLA-4 [CD49d/CD29]) played a crucial role in neutrophil crawling and emigration to VEGF-A. Isolated CD49d(+) neutrophils featured increased chemokinesis but not chemotaxis compared with CD49d(-) neutrophils in the presence of VEGF-A. Finally, by targeting the integrin α4 subunit (CD49d) in a transplantation-based angiogenesis model that used avascular pancreatic islets transplanted to striated muscle, we demonstrated that inhibiting the recruitment of circulating proangiogenic neutrophils to hypoxic tissue impairs vessel neoformation. Thus, angiogenesis can be modulated by targeting cell-surface receptors specifically involved in VEGF-A-dependent recruitment of proangiogenic neutrophils without compromising recruitment of the neutrophil population involved in the immune response to pathogens.

    National Category
    Physiology
    Identifiers
    urn:nbn:se:uu:diva-265201 (URN)10.1182/blood-2015-03-631572 (DOI)000366389200012 ()26286848 (PubMedID)
    Funder
    Swedish Research CouncilThe Royal Swedish Academy of SciencesMagnus Bergvall FoundationSwedish Diabetes AssociationÅke Wiberg FoundationRagnar Söderbergs stiftelseKnut and Alice Wallenberg Foundation
    Available from: 2015-10-25 Created: 2015-10-25 Last updated: 2018-01-10Bibliographically approved
  • 130.
    Massena, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Christoffersson, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Hjertström, Elina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zcharia, Eyal
    Vlodavsky, Israel
    Ausmees, Nora
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Rolny, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Li, Jin-Ping
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    A chemotactic gradient sequestered on endothelial heparan sulfate induces directional intraluminal crawling of neutrophils2010In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 116, no 11, p. 1924-1931Article in journal (Refereed)
    Abstract [en]

    During infection, chemokines sequestered on endothelium induce recruitment of circulating leukocytes into the tissue where they chemotax along chemokine gradients toward the afflicted site. The aim of this in vivo study was to determine whether a chemokine gradient was formed intravascularly and influenced intraluminal neutrophil crawling and transmigration. A chemokine gradient was induced by placing a macrophage inflammatory protein-2 (MIP-2)-containing (CXCL2) gel on the cremaster muscle of anesthetized wild-type mice or heparanase-overexpressing transgenic mice (hpa-tg) with truncated heparan sulfate (HS) side chains. Neutrophil-endothelial interactions were visualized by intravital microscopy and chemokine gradients detected by confocal microscopy. Localized extravascular chemokine release (MIP-2 gel) induced directed neutrophil crawling along a chemotactic gradient immobilized on the endothelium and accelerated their recruitment into the target tissue compared with homogeneous extravascular chemokine concentration (MIP-2 super-fusion). Endothelial chemokine sequestration occurred exclusively in venules and was HS-dependent, and neutrophils in hpa-tg mice exhibited random crawling. Despite similar numbers of adherent neutrophils in hpa-tg and wild-type mice, the altered crawling in hpa-tg mice was translated into decreased number of emigrated neutrophils and ultimately decreased the ability to clear bacterial infections. In conclusion, an intravascular chemokine gradient sequestered by endothelial HS effectively directs crawling leukocytes toward transmigration loci close to the infection site.

  • 131.
    Massena, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Lomei, Jalal
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Mortier, Anneleen
    University of Leuven, Belgium.
    Etheridge, Leah
    University of York, England.
    Rot, Antal
    University of York, England.
    Proost, Paul
    University of Leuven, Belgium.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Chemokine transport across the vessel wall and presentation to circulation leukocytes are regulated by vascular permeability, DARC and PAD released during inflammationManuscript (preprint) (Other (popular science, discussion, etc.))
    Abstract [en]

    Increased vascular permeability and consequent leakage of plasma and macromolecules through endothelial cell junctions is a hallmark of inflammation. The physiological importance of this event for leukocyte recruitment has been controversial, but it might have a role in chemokine transport into blood vessels and consequently for the recruitment of circulating leukocytes. Elevated amounts of peptidyl arginine deiminases (PAD) and of their citrullinated products associate with autoimmune disorders, chronic inflammation and cancer. The role of citrullination in the inflamed microenvironment is debated, but it might be an innate mechanism for infiltrating leukocytes to resolve inflammation. In this study we investigated if increased vascular permeability facilitated the influx of chemokines from tissue into post-capillary venules, thereby affecting leukocyte recruitment. Vascular permeability and chemokine influx into post-capillary venules were simultaneously monitored by real-time in vivo confocal microscopy of the mouse cremaster muscle. We found that increased venular permeability induced by histamine, correlated with accelerated influx of the fluorescently labeled chemokine CXC ligand 2 (CXCL2/MIP-2) into post-capillary venules, which accumulated predominantly at endothelial cell junctions. Consequently, neutrophil adhesion was accelerated leading to increased neutrophil extravasation. In situ inhibition of caveolae-mediated transcytosis by filipin had no significant effect on chemokine influx to post-capillary venules, indicating that chemokine traffic across the venular wall is independent of caveolar transport. Nevertheless, neutrophil recruitment was prevented in filipin-treated mice as transmigrating neutrophils were trapped on endothelial cell domes and failed to finalize transmigration. Furthermore, we used this real-time in vivo model for studying the role of the atypical chemokine receptor 1 (DARC/ACKR1) in chemokine transport and availability. We show that the absence of DARC/ACKR1 (ACKR1-/- mice) does not impair chemokine transport. Instead it leads to increased seric levels of chemokine and increased intravascular chemokine sequestration. As a result, high numbers of firmly adherent neutrophils were found in post-capillary venules. Intraluminal neutrophil crawling was though abrogated and neutrophil transmigration prevented. Finally, we studied the role of chemokine citrullination by leukocyte-derived PAD in the inflamed tissue. The transport of citrullinated CXC ligand 8 (CXCL8/IL-8) across the venular wall, its immobilization on the luminal endothelium, and subsequent leukocyte recruitment, were monitored by real time imaging. Chemokine citrullination inhibited its transport from the inflamed tissue into blood vessels, impeding their immobilization on the luminal endothelium. Reduced intravascular chemokine bioavailability dampened leukocyte recruitment. Altogether these findings demonstrate that changes in vascular permeability regulate inflammation by affecting abluminal-to-luminal chemokine transport and thereby leukocyte recruitment to tissue. Furthermore, DARC/ACKR1 plays an important role in neutrophil recruitment by controlling intravascular chemokine availability and by shaping the intravascular chemokine gradient necessary for efficient neutrophil recruitment. Finally, citrullination of chemokines by PAD in the inflamed tissue inhibits chemokine transport into blood vessels and luminal presentation to circulating leukocytes, which dampens leukocyte recruitment

  • 132.
    Massena, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Mortier, Anneleen
    Department of Microbiology and Immunology, Laboratory of Molecular Immunology, Rega Institute Leuven, Belgium.
    Proost, Paul
    Department of Microbiology and Immunology, Laboratory of Molecular Immunology, Rega Institute Leuven, Belgium.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Increased vascular permeability facilitates vascular influx of chemokines and accelerates recruitment of circulating neutrophilsManuscript (preprint) (Other academic)
  • 133.
    Massena, Sara
    et al.
    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.
    Intravascular Leukocyte Chemotaxis: The Rules of Attraction2012In: Hematology - Science and Practice / [ed] Charles Lawrie, INTECH, 2012, p. 229-252Chapter in book (Other academic)
  • 134.
    Melville, Jaqueline M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    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.
    Renal oxygenation during haemorrhage is not aggravated by angiotensin II AT1-receptor blockade2016In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 216, no 2, p. 153-155Article in journal (Refereed)
  • 135.
    Nensén, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Role of carbonic anhydrase in acute recovery following renal ischemia reperfusion injury2017In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 31Article in journal (Other academic)
  • 136.
    Nikpour, Maryam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gustafsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Vågesjö, Evelina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Seignez, Cedric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Giraud, Antoine
    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.
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Shb deficiency in endothelium but not in leukocytes is responsible for impaired vascular performance during hindlimb ischemia.2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 214, no 2, p. 200-209Article in journal (Refereed)
    Abstract [en]

    Aim: Myeloid cells have been suggested to participate in angiogenesis and regulation of vascular function. Shb-deficient mice display both vascular and myeloid cell abnormalities with possible consequences for recovery after hindlimb ischemia. This study was conducted in order to assess the contribution of Shb-deficiency in myeloid cells to impaired vascular function in ischemia. Methods: Wild type and Shb-deficient mice were subjected to peritoneal VEGFA followed by intraperitoneal lavage, after which blood and peritoneal cells were stained for myeloid markers. VEGFA-induced leukocyte recruitment to cremaster muscle was investigated using intravital microscopy of both mouse strains. Blood flow after femoral artery ligation was determined on chimeric mice after bone marrow transplantation. Results: No differences in neutrophil numbers or cell surface phenotypes were detected. Moreover, neutrophil extravasation in VEGFA-activated cremaster muscle was unaffected by Shb deficiency. However, blood and peritoneal CXCR4+ monocytes/macrophages were reduced in response to intraperitoneal VEGFA but not LPS in the absence of Shb. Furthermore, the macrophage population in ischemic muscle was unaffected by Shb-deficiency after two days but reduced seven days after injury. The bone marrow transplantation experiments revealed that mice with wild type vasculature showed better blood flow than those with Shb-deficient vasculature irrespective of leukocyte genotype. Conclusion: The observed aberrations in myeloid cell properties in Shb-deficient mice are likely consequences of an abnormal vascular compartment and are not responsible for reduced muscle blood flow. Structural vascular abnormalities seem to be the primary cause of poor vascular performance under provoked vascular stress in this genetic model.

  • 137.
    Nilsson, Line
    et al.
    Aarhus Univ, Dept Clin Med, Aarhus, Denmark..
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Linkoping Univ, Dept Med Hlth Sci, Div Drug Res, Linkoping, Sweden..
    Nørregaard, Rikke
    Aarhus Univ, Dept Clin Med, Aarhus, Denmark..
    15-Deoxy-Delta(12,14)-prostaglandin J(2) Exerts Antioxidant Effects While Exacerbating Inflammation in Mice Subjected to Ureteral Obstruction2017In: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, article id 3924912Article in journal (Refereed)
    Abstract [en]

    Urinary obstruction is associated with inflammation and oxidative stress, leading to renal dysfunction. Previous studies have shown that 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) has both antioxidant and anti-inflammatory effects. Using a unilateral ureteral obstruction (UUO) mouse model, we examined the effects of 15d-PGJ(2) on oxidative stress and inflammation in the kidney. Mice were subjected to UUO for 3 days and treated with 15d-PGJ(2). Protein and RNA expression were examined using immunoblotting and qPCR. 15d-PGJ(2) increased NF-E2-related nuclear factor erythroid-2 (Nrf2) protein expression in response to UUO, and heme oxygenase 1 (HO-1), a downstream target of Nrf2, was induced by 15d-PGJ(2). Additionally, 15d-PGJ(2) prevented protein carbonylation, a UUO-induced oxidative stress marker. Inflammation, measured by nuclear NF-kappa B, F4/80, and MCP-1, was increased in response to UUO and further increased by 15d-PGJ(2). Renal injury was aggravated by 15d-PGJ(2) treatment as measured by kidney injury molecule-1 (KIM-1) and cortical caspase 3 content. No effect of 15d-PGJ(2) was observed on renal function in mice subjected to UUO. This study illustrates differentiated functioning of 15d-PGJ(2) on inflammation and oxidative stress in response to obstructive nephropathy. High concentrations of 15d-PGJ(2) protects against oxidative stress during 3-day UUO in mice; however, it aggravates the associated inflammation.

  • 138.
    Nordquist, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Physiology education and the linguistic jungle of science2008In: Advances in Physiology Education, ISSN 1043-4046, E-ISSN 1522-1229, Vol. 32, no 3, p. 173-174Article, review/survey (Other academic)
  • 139.
    Nordquist, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Brown, Russell
    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.
    Sjöquist, Mats
    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.
    Proinsulin C-peptide reduces diabetes-induced glomerular hyperfiltration via efferent arteriole dilation and inhibition of tubular sodium reabsorption2009In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 297, no 5, p. F1265-F1272Article in journal (Refereed)
    Abstract [en]

    C-peptide reduces diabetes-induced glomerular hyperfiltration in diabetic patients and experimental animal models. However, the mechanisms mediating the beneficial effect of C-peptide remain unclear. We investigated whether altered renal afferent-efferent arteriole tonus or alterations in tubular Na+ transport (T(Na)) in response to C-peptide administration mediate the reduction of diabetes-induced glomerular hyperfiltration. Glomerular filtration rate, filtration fraction, total and cortical renal blood flow, total kidney O2 consumption (QO2), T(Na), fractional Na+ and Li+ excretions, and tubular free-flow and stop-flow pressures were measured in anesthetized adult male normoglycemic and streptozotocin-diabetic Sprague-Dawley rats. The specific effect of C-peptide on transport-dependent QO2 was investigated in vitro in freshly isolated proximal tubular cells. C-peptide reduced glomerular filtration rate (-24%), stop-flow pressure (-8%), and filtration fraction (-17%) exclusively in diabetic rats without altering renal blood flow. Diabetic rats had higher baseline T(Na) (+40%), which was reduced by C-peptide. Similarly, C-peptide increased fractional Na+ (+80%) and Li+ (+47%) excretions only in the diabetic rats. None of these parameters was affected by vehicle treatments in either group. Baseline QO2 was 37% higher in proximal tubular cells from diabetic rats than controls and was normalized by C-peptide. C-peptide had no effect on ouabain-pretreated diabetic cells from diabetic rats. C-peptide reduced diabetes-induced hyperfiltration via a net dilation of the efferent arteriole and inhibition of tubular Na+ reabsorption, both potent regulators of the glomerular net filtration pressure. These findings provide new mechanistic insight into the beneficial effects of C-peptide on diabetic kidney function.

  • 140.
    Nordquist, Lina
    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.
    Liss, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Shoji, Kumi
    Nangaku, Masaomi
    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.
    Activation of Hypoxia-Inducible Factors Prevents Diabetic Nephropathy2015In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 26, no 2, p. 328-338Article in journal (Refereed)
    Abstract [en]

    Hyperglycemia results in increased oxygen consumption and decreased oxygen tension in the kidney. We tested the hypothesis that activation of hypoxia-inducible factors (HIFs) protects against diabetes-induced alterations in oxygen metabolism and kidney function. Experimental groups consisted of control and streptozotocin-induced diabetic rats treated with or without chronic cobalt chloride to activate HIFs. We elucidated the involvement of oxidative stress by studying the effects of acute administration of the superoxide dismutase mimetic tempol. Compared with controls, diabetic rats displayed tissue hypoxia throughout the kidney, glomerular hyperfiltration, increased oxygen consumption, increased total mitochondrial leak respiration, and decreased tubular sodium transport efficiency. Diabetic kidneys showed proteinuria and tubulointerstitial damage. Cobalt chloride activated HIFs, prevented the diabetes-induced alterations in oxygen metabolism, mitochondrial leak respiration, and kidney function, and reduced proteinuria and tubulointerstitial damage. The beneficial effects of tempol were less pronounced after activation of HIFs, indicating improved oxidative stress status. In conclusion, activation of HIFs prevents diabetes-induced alteration in kidney oxygen metabolism by normalizing glomerular filtration, which reduces tubular electrolyte load, preventing mitochondrial leak respiration and improving tubular transport efficiency. These improvements could be related to reduced oxidative stress and account for the reduced proteinuria and tubulointerstitial damage. Thus, pharmacologic activation of the HIF system may prevent development of diabetic nephropathy.

  • 141.
    Nordquist, Lina
    et al.
    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 Radiology, Oncology and Radiation Science, Radiology.
    Henriksnas, J.
    Stay-at-home laboratory experiments - A case study of student motivation2006In: WMSCI 2006: 10TH WORLD MULTI-CONFERENCE ON SYSTEMICS, CYBERNETICS AND INFORMATICS, VOL VII, PROCEEDINGS, 2006, p. 114-116Conference paper (Refereed)
    Abstract [en]

    Background: Studies have reported that as many as 60 % of all students learn in a practical manner, rather than theoretically. However, Internet courses, tight budgets and increasing student numbers augments the demand for laboratory experiments carried out off the university premises. Methods: This pilot study was performed to investigate whether laboratory experiments in physiology performed at home are motivating for, stimulates depth understanding and increases student learning. Pharmacy students were recruited to the project from a five-week physiology course, and were given instruc tions on four stay-at-home experiments. These experiments were then discussed at a seminar. In conjunction to this seminar, a simple survey was filled in by the students. Comments: Our results indicated that this method of learning would be appreciated by the students. Stay-at-home laboratory experiments can never take the place of ordinary laboratory experiments, but could be beneficial as a supplement, not the least by introducing an everyday perspective to the students, allowing them to reflect on connections and relations in every day life.

  • 142.
    Nordquist, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Isaksson, Britta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sjöquist, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    The effect of amiloride during infusion of oxytocin in male sprague-dawley rats: a study of a possible intrarenal target site for oxytocin2008In: Clinical and experimental hypertension (1993, Print), ISSN 1064-1963, E-ISSN 1525-6006, Vol. 30, no 2, p. 151-158Article in journal (Refereed)
    Abstract [en]

    A possible natriuretic mechanism of action of oxytocin was investigated in male Sprague-Dawley rats. The effects of an intravenous bolus injection of amiloride on urine volume, potassium and sodium excretion, and osmolality were measured with and without an intravenous infusion of oxytocin in saline. Control values were obtained during the infusion of saline. Amiloride administered during an oxytocin infusion increased sodium excretion from 0.1 +/- 0.0 to 16.6 +/- 2.1 micromol/min. In animals treated with amiloride only, the sodium excretion was 4.5 +/- 0.8 micromol/min. The administration of oxytocin only resulted in a sodium excretion of 1.2 +/- 0.3 micromol/min. After the administration of oxytocin, amiloride increased urinary flow from 4.3 +/- 0.6 microl/min to 48.8 +/- 6.1 microl/min. In animals treated with amiloride only, the flow after the bolus dose was 17.7 +/- 1.8 microl/min. The administration of oxytocin only resulted in a flow of 8.5 +/- 1.6 microl/min. The amiloride-caused change in potassium excretion was not inhibited by oxytocin. In summary, the effects of amiloride were not inhibited by the actions of oxytocin. Amiloride administrated after reaching a near steady-state effect of oxytocin was found to give rise to an effect far greater than that after the administration of oxytocin or amiloride alone. It is concluded that the intrarenal natriuretic mechanisms of oxytocin do not emanate from the amiloride-sensitive sodium channels.

  • 143.
    Nordquist, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Johansson, Magnus
    Proinsulin C-peptide: friend or foe in the development of diabetes-associated complications?2008In: Vascular health and risk management, ISSN 1178-2048, Vol. 4, no 6, p. 1283-1288Article, review/survey (Other academic)
    Abstract [en]

    The proinsulin connecting peptide, C-peptide, is a cleavage product of insulin synthesis that is co-secreted with insulin by pancreatic beta-cells following glucose stimulation. Recombinant insulin, used in the treatment of diabetes, lacks C-peptide and preclinical and clinical studies suggest that lack of C-peptide may exacerbate diabetes-associated complications. In accordance with this, several studies suggest that C-peptide has beneficial effects in a number of diabetes-associated complications. C-peptide has been shown to prevent diabetic neuropathy by improving endoneural blood flow, preventing neuronal apoptosis and by preventing axonal swelling. In the vascular system, C-peptide has been shown to prevent vascular dysfunction in diabetic rats, and to possess anti-proliferative effects on vascular smooth muscle cells, which may prevent atherosclerosis. However, C-peptide depositions have been found in arteriosclerotic lesions of patients with hyperinsulinemic diabetes and C-peptide has been shown to induce pro-inflammatory mediators, such as nuclear factor kappa B, inducible nitric oxide synthase, and cyclooxygenase-2, indicating that C-peptide treatment could be associated with side-effects that may accelerate the development of diabetes-associated complications. This review provides a brief summary of recent research in the field and discusses potential beneficial and detrimental effects of C-peptide supplementation.

  • 144.
    Nordquist, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Lai, En Yin
    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.
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Persson, A Erik G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    C-peptide constricts pancreatic islet arterioles in diabetic, but not normoglycaemic mice2008In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 24, no 2, p. 165-168Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Pancreatic islet blood flow is regulated separately from that of the exocrine pancreas, and a consistent finding during impaired glucose tolerance is an increased blood perfusion. The aim of the present study was to investigate whether C-peptide affects pancreatic islet arterioles in normal and diabetic mice.

    MATERIALS AND METHODS: Control and diabetic C57-Bl mice were studied after 2 weeks of alloxan-induced diabetes. Islet arterioles were dissected and microperfused with Dulbecco's modified Eagle medium (DMEM) solution. The effect of luminal application of mouse C-peptide was investigated.

    RESULTS: C-peptide reduced the diameter of islet arterioles from diabetic mice (-10+/-4%, P<0.05) compared to base-line values, whilst arterioles from normoglycaemic animals did not respond to C-peptide (P=0.2).

    CONCLUSION: These findings suggest a role for C-peptide in the regulation of islet blood flow, especially during conditions with impaired glucose tolerance.

  • 145.
    Nordquist, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Lai, En Yin
    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.
    Patzak, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Persson, A Erik G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Proinsulin C-peptide constricts glomerular afferent arterioles in diabetic mice: A potential renoprotective mechanism2008In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 294, no 3, p. R836-R841Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: an increased glomerular filtration rate (GFR) has been postulated as a potential mechanism involved in the progression of diabetic nephropathy. Studies suggest that C-peptide exerts a renoprotective effect on diabetes. The peptide decreases hyperfiltration in patients with type 1 diabetes, as well as in diabetic animal models. In this study, we investigated whether C-peptide causes a change in arteriolar diameter.

    RESEARCH DESIGN AND METHODS: C57-Bl mice were made diabetic by means of a single intravenous injection of alloxan 2 wk prior to the experiment. Age-matched normoglycemic mice served as controls. Afferent arterioles, intact with the glomeruli, were dissected and microperfused. The effect of luminal application of C-peptide, compared with scrambled C-peptide or vehicle, was investigated. The effect of the Rho-kinase inhibitor Y-27632 was also investigated.

    RESULTS: C-peptide constricted afferent arterioles in diabetic mice by -27% compared with the control value. Normoglycemic arterioles administered C-peptide displayed a delayed and minute response (-4%). Scrambled C-peptide or vehicle administration, whether administered to hyperglycemic or normoglycemic mice, did not induce any effect. Addition of Y-27632 abolished the effect of C-peptide.

    CONCLUSION: C-peptide induces constriction of afferent arterioles in diabetic mice. This can reduce enhanced GFR and may be one of the mechanisms in the renoprotective action of C-peptide in diabetes.

  • 146.
    Nordquist, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Liss, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    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.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Hypoxia in the diabetic kidney is independent of advanced glycation end-products2013In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 765, p. 185-193Article in journal (Refereed)
    Abstract [en]

    Sustained hyperglycemia is closely associated with increased risk to develop nephropathy. We have previously reported alterations in the intrarenal oxygen metabolism already after the early onset of diabetes. Furthermore, formation of advanced glycation end-products (AGE) is postulated as a major contributor to diabetic nephropathy. We therefore investigated the possible relationship between altered oxygen metabolism and AGE in diabetic kidneys.Normoglycemic and streptozotocin-diabetic rats with and without chronic treatment with aminoguanidine (AGE inhibitor; 600 mg/kg bw/24 h in drinking water) or L-N6-(1-Iminoethyl)lysine (L-NIL, iNOS inhibitor, 1 mg/kg bw/24 h in drinking water) were studied 2 weeks after induction of diabetes. Glomerular filtration rate (GFR) was estimated by inulin clearance, oxygen tension (pO2) and interstitial pH by microelectrodes and regional renal blood flow (RBF) by laser-Doppler. Histological changes were evaluated on fixed tissue.Glomerular hyperfiltration was unaffected by aminoguanidine, whereas L-NIL normalized GFR in diabetic rats. pO2 and interstitial pH, but not RBF, were lower in both kidney cortex and medulla compared to control rats, but was unaffected by both chronic treatments. Urinary protein excretion was higher in diabetic rats and unaffected by L-NIL, whereas aminoguanidine paradoxically increased this parameter. Damage scores were similar in all groups.In conclusion, diabetes-induced alterations in intrarenal oxygen metabolism are independent of the AGE pathway, and precede any morphological changes. These findings highlight the early stage of diabetes as being a metabolic disorder also in the kidney.

  • 147.
    Nordquist, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Moe, Erika
    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.
    The C-peptide fragment EVARQ reduces glomerular hyperfiltration in streptozotocin-induced diabetic rats2007In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 23, no 5, p. 400-405Article in journal (Refereed)
    Abstract [en]

    BACKGROUND

    Initially, diabetes is commonly associated with an increased glomerular filtration rate (GFR), a potential mechanism involved in the progression of diabetic nephropathy. Several studies have reported reno-protective effects of C-peptide. C-peptide reduces diabetes-induced hyperfiltration, as well as renal hypertrophy and albuminuria. In order to gain further understanding of these effects, it is very important to localize the active sites within the C-peptide molecule. This study was designed to elucidate the effects of the C-peptide fragment EVARQ on kidney function, blood pressure and blood glucose levels in diabetic rats in vivo.

    METHODS

    The study was performed on adult inactin-anaesthetized male Sprague-Dawley rats. Two weeks prior to the experiment, diabetes was induced by a single intravenous injection of streptozotocin (55 mg/kg BW). After recovery and recording of baseline values, vehicle, C-peptide (50 pmol . kg BW(-1).h(-1)) or EVARQ (500 pmol.kg BW(-1).h(-1)) was continuously administered for a total of 100 min.

    RESULTS

    Before substance administration, all diabetic groups displayed a pronounced hyperfiltration as compared to the control rats. Continuous administration of both C-peptide and EVARQ reduced the diabetes-induced hyperfiltration within an hour. Furthermore, blood pressure was only reduced in diabetic rats that were given C-peptide, whereas the blood glucose decreased in the diabetic groups that were given either C-peptide or EVARQ.

    CONCLUSIONS

    The present study shows that administration of the C-peptide fragment EVARQ has similar effects on GFR and blood glucose levels as the intact C-peptide molecule, suggesting at least one active site within this region.

  • 148.
    Nordquist, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Diabetes-induced alterations in renal medullary microcirculation and metabolism2007In: Current diabetes reviews, ISSN 1573-3998, Vol. 3, no 1, p. 53-65Article, review/survey (Refereed)
    Abstract [en]

    Diabetes-induced renal complications, i.e. diabetes nephropathy, are a major cause of morbidity and mortality. The exact mechanisms mediating the negative influence of hyperglycemia on renal function are unclear, although several hypotheses have been postulated. Cellular mechanisms include glucose-induced excessive formation of reactive oxygen species, increased glucose flux through polyol pathway and pentose phosphate shunt, formation of advanced glycation end-products and activation of protein kinase C and NADPH oxidase. However, the renal effects in vivo of each and every one of these mechanisms are less clear, although recent studies have shown several major alterations predominantly in the renal medulla as a result of sustained hyperglycemia. Already during normal conditions, the renal medulla has a remarkably low oxygen tension (PO2) and a high degree of non-oxygen dependent energy metabolism. Alterations in either blood perfusion or oxygen delivery to the medullary region will have significant effects on both regional metabolism and total kidney function. Recently, sustained hyperglycemia has been shown to induce a pronounced reduction in preferentially renal medullary PO2. This review will present the current knowledge of diabetes-induced alterations in renal medullary metabolism and function, but also discuss future targets for prevention of diabetic nephropathy.

  • 149.
    Nordquist, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Andresen, Bradley T
    Renal and vascular benefits of C-peptide: Molecular mechanisms of C-peptide action2008In: Biologics, ISSN 1177-5475, Vol. 2, no 3, p. 441-452Article in journal (Refereed)
    Abstract [en]

    C-peptide has long been thought to be an inert byproduct of insulin production, but it has become apparent, and accepted, that C-peptide has important biological properties. C-peptide displays beneficial effects in many tissues affected by diabetic complications, such as increased peripheral blood flow and protection from renal damage. However, the mechanisms mediating these effects remain unclear. C-peptide interacts with cellular membranes at unidentified sites distinctive of the insulin family of receptors, and signals to multiple targets known to play a role in diabetes and diabetic complications, such as Na(+)/K(+)-ATPase and NOS. In general, the physiological and molecular effects of C-peptide resemble insulin, but C-peptide also possesses traits separate from those of insulin. These basic studies have been confirmed in human studies, suggesting that C-peptide may lend itself to clinical applications. However, the molecular and physiological properties of C-peptide are not completely elucidated, and large clinical studies have not begun. In order to further these goals, we critically summarize the current state of knowledge regarding C-peptide's renal and vascular effects and the molecular signaling of C-peptide.

  • 150.
    Nordquist, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Roxhed, Niclas
    Griss, Patrick
    Stemme, Göran
    Novel microneedle patches for active insulin delivery are efficient in maintaining glycaemic control: an initial comparison with subcutaneous administration2007In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 24, no 7, p. 1381-1388Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Good glycaemic control is essential to minimize the risk for diabetes-induced complications. Also, compliance is likely to be higher if the procedure is simple and painless. This study was designed to validate painless intradermal delivery via a patch-like microneedle array.

    MATERIALS AND METHODS: Diabetes was induced by an intravenous injection of streptozotocin (50 mg/kg bw) in adult male Sprague Dawley rats. Plasma insulin and blood glucose were measured before, during and after subcutaneous or intradermal (microneedles) infusion of insulin (0.2 IU/h) under Inactin-anaesthesia.

    RESULTS: Before insulin administration, all animals displayed a pronounced hyperglycaemia (19 +/- 1 mM; 359 mg/dl). Administration of insulin resulted in a reduced plasma glucose independently of administration route (subcutaneous 7.5 +/- 4.2, n = 9, and intradermal 11 +/- 1.8, n = 9 after 240 min), but with less errors of the mean in the intradermal group. In the intradermal group, plasma insulin was increased in all latter measurements (72 +/- 22, 81 +/- 34, and 87 +/- 20 microIU/ml), as compared to the first measurement (26 +/- 13). In the subcutaneous group, plasma insulin was elevated during the last measurement (to 154 +/- 3.5 microIU/ml from 21 +/- 18).

    CONCLUSION: This study presents a novel possibility of insulin delivery that is controllable and requires minimal training. This treatment strategy could improve compliance, and thus be beneficial for patients' glycaemic control.

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