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  • 251.
    Carlsson, Per-Ola
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Nordin, Astrid
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Palm, Frredrik
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    pH is decreased in transplantated rat pancreatic islets2003Inngår i: Am J Physiol Endocrinol Metab, Vol. 284, s. E499-Artikkel i tidsskrift (Fagfellevurdert)
  • 252.
    Carlsson, Per-Ola
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Olsson, R
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Kallskog, O
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Bodin, B
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Andersson, A
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Jansson, L
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Glucose-induced islet blood flow increase in rats: interaction betweennervous and metabolic mediators.2002Inngår i: Am J Physiol Endocrinol Metab, Vol. 283, s. E457-Artikkel i tidsskrift (Fagfellevurdert)
  • 253.
    Carlsson, Per-Ola
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Ostenson, C-G
    Efendic, S
    Langel, ü
    Jansson, L
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Pituitary adenylate cyclase activating polypeptide (PACAP) redistributes the blood within the pancreas of anesthetized rats1996Inngår i: Regul Pept, Vol. 63, s. 123-Artikkel i tidsskrift (Fagfellevurdert)
  • 254.
    Carlsson, Per-Ola
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Palm, Fredrik
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Oxygen tension in isolated transplanted rat islets and in islets of rat whole-pancreas transplants.2002Inngår i: Transpl Int, Vol. 15, s. 581-585Artikkel i tidsskrift (Fagfellevurdert)
  • 255.
    Carlsson, Per-Ola
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Palm, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Andersson, Arne
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Liss, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Chronically decreased oxygen tension in rat pancreatic islets transplantedunder the kidney capsule2000Inngår i: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 69, nr 5, s. 761-766Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: A factor of potential importance in the failure of islet grafts is poor or inadequate engraftment of the islets in the implantation organ. This study measured the oxygen tension and blood perfusion in 1-, 2-, and 9-month-old islet grafts. METHODS: The partial pressure of oxygen was measured in pancreatic islets transplanted beneath the renal capsule of diabetic and nondiabetic recipient rats with a modified Clark electrode (outer tip diameter 2-6 microm). The size of the graft (250 islets) was by purpose not large enough to cure the diabetic recipients. The oxygen tension in islets within the pancreas was also recorded. Blood perfusion was measured with the laser-Doppler technique. RESULTS: Within native pancreatic islets, the partial pressure of oxygen was approximately 40 mm Hg (n=8). In islets transplanted to nondiabetic animals, the oxygen tension was approximately 6-7 mm Hg 1, 2, and 9 months posttransplantation. No differences could be seen between the different time points after transplantation. In the diabetic recipients, an even more pronounced decrease in graft tissue oxygen tension was recorded. The mean oxygen tension in the superficial renal cortex surrounding the implanted islets was similar in all groups (approximately 15 mm Hg). Intravenous administration of glucose (0.1 gxkg(-1)x min(-1)) did not affect the oxygen tension in any of the investigated tissues. The islet graft blood flow was similar in all groups, measuring approximately 50% of the blood flow in the kidney cortex. CONCLUSION: The oxygen tension in islets implanted beneath the kidney capsule is markedly lower than in native islets up to 9 months after transplantation. Moreover, persistent hyperglycemia in the recipient causes an even further decrease in graft oxygen tension, despite similar blood perfusion. To what extent this may contribute to islet graft failure remains to be determined.

  • 256.
    Carlsson, Per-Ola
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Palm, Fredrik
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Andersson, Arne
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Liss, Per
    Institutionen för onkologi, radiologi och klinisk immunologi.
    Markedly decreased oxygen tension in transplanted rat pancreatic islets irrespective of the implantation site.2001Inngår i: Diabetes, ISSN 0012-1797, Vol. 50, nr 3, s. 489-95Artikkel i tidsskrift (Annet vitenskapelig)
  • 257.
    Carlsson, Per-Ola
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Palm, Fredrik
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Mattsson, Göran
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Low revascularization of experimentally transplanted human pancreatic islets.2002Inngår i: J Clin Endocrino Metab, Vol. 87, nr 12, s. 5418-5423Artikkel i tidsskrift (Fagfellevurdert)
  • 258.
    Carlsson, Per-Ola
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Sandler, S
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Jansson, L
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Influence of the neurotoxin capsaicin on rat pancreatic islets in culture, and on the pancreatic islet blood flow of rats1996Inngår i: Eur J Pharmacol, Vol. 312, s. 75-Artikkel i tidsskrift (Fagfellevurdert)
  • 259.
    Carlsson, Per-Ola
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Sandler, S
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Jansson, L
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Pancreatic islet blood perfusion in the nonobese diabetic mouse: Diabetes-prone female mice exhibit a higher blood flow compared with male mice in the prediabetic phase1998Inngår i: Endocrinology, Vol. 139, s. 3534-Artikkel i tidsskrift (Fagfellevurdert)
  • 260.
    Carlsson, Per-Ola
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Schwarcz, Erik
    Korsgren, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Le Blanc, Katarina
    Preserved Beta-Cell Function in Type 1 Diabetes by Mesenchymal Stromal Cells2015Inngår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, nr 2, s. 587-592Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The retention of endogenous insulin secretion in type 1 diabetes is an attractive clinical goal, which opens possibilities for long-term restoration of glucose metabolism. Mesenchymal stromal cells (MSCs) constitute, based on animal studies, a promising interventional strategy for the disease. This prospective clinical study describes the translation of this cellular intervention strategy to patients with recent onset type 1 diabetes. Twenty adult patients with newly diagnosed type 1 diabetes were enrolled and randomized to MSC treatment or to the control group. Residual beta-cell function was analyzed as C-peptide concentrations in blood in response to a mixed meal tolerance test (MMTT) at one-year follow-up. In contrast to the patients in the control arm, who showed loss in both C-peptide peak values and C-peptide when calculated as area under the curve during the first year, these responses were preserved or even increased in the MSC-treated patients. Importantly, no side effects of MSC treatment were observed. We conclude that autologous MSC treatment in new onset type 1 diabetes constitute a safe and promising strategy to intervene in disease progression and preserve beta-cell function.

  • 261.
    Carlsson, Per-Ola
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Stridsberg, M
    Institutionen för medicinska vetenskaper.
    Jansson, L
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Influence of corticotropin-releasing factor on pancreatic islet blood flow in different regions of the rat pancreas.1995Inngår i: Digestion, Vol. 56, s. 242-Artikkel i tidsskrift (Fagfellevurdert)
  • 262.
    Carlström, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Causal link between neonatal hydronephrosis and later development of hypertension2010Inngår i: Clinical and experimental pharmacology & physiology, ISSN 0305-1870, E-ISSN 1440-1681, Vol. 37, nr 2, s. E14-E23Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    1. Although congenital ureteral obstruction is a common disorder in infants, its pathophysiology remains poorly understood and its clinical management continues to be debated. During the past decade, the surgical management of non-symptomatic hydronephrosis in children has become more conservative, but the long-term physiological consequences of this new policy are unclear. 2. In experimental models with complete ureteral obstruction, tubular atrophy and interstitial inflammation occur rapidly. Although this type of obstruction is very rare in clinical practice, it is often referred to in clinical discussions. New studies, using a model with chronic partial ureteral obstruction, have demonstrated that hydronephrosis is associated with renal injuries and is causally related to hypertension. 3. The mechanisms underlying the development of hypertension in experimental hydronephrosis are complex and involve changes in both the renin-angiotensin system and renal sympathetic nerve activity. Furthermore, oxidative stress and nitric oxide deficiency in the diseased kidney, with consequent resetting of the tubuloglomerular feedback mechanism, appear to play a pivotal role in the development and maintenance of hypertension. 4. In view of the new knowledge regarding the long-term effects of partial ureteral obstruction, today's non-operative management of hydronephrosis should be reconsidered to prevent obstructive nephropathy and hypertension in later life.

  • 263.
    Carlström, Mattias
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Development of Salt-Sensitive Hypertension in Hydronephrosis2008Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Hydronephrosis, due to ureteropelvic junction obstruction, is a common condition in infants with an incidence of approximately 0.5-1%. During the last decade, the surgical management of non-symptomatic hydronephrosis has become more conservative, and the long-term physiological consequences of this new policy are unclear. The overall aim of this thesis was to determine whether there is a link between hydronephrosis and the development of hypertension. Hydronephrosis was induced by partial ureteral obstruction in 3-week old rats or mice. In the adult animals, blood pressure was measured telemetrically during different sodium conditions and the renal function was evaluated. Both species developed salt-sensitive hypertension and histopathological changes (i.e. fibrosis, inflammation, glomerular and tubular changes) that correlated with the degree of hydronephrosis. An abnormal renal excretion pattern with increased diuresis and impaired urine concentrating ability was observed in hydronephrosis. The mechanisms were primarily located to the diseased kidney, as relief of the obstruction attenuated blood pressure and salt-sensitivity. Increased renin angiotensin system activity, due to ureteral obstruction, might be involved in the development but not necessary the maintenance of hypertension. Hydronephrotic animals displayed reduced nitric oxide availability, which might be due to increased oxidative stress in the diseased kidney. Renal nitric oxide deficiency and subsequent resetting of the tubuloglomerular feedback mechanism, appeared to have an important role in the development of hypertension. In conclusion, experimental hydronephrosis, induced by partial ureteral obstruction, provides a new model for studies of salt-sensitive hypertension. Furthermore, the new findings imply that the current conservative treatment strategy in hydronephrosis should be reconsidered in favour of treatment that is more active, in order to prevent the development of renal injury and hypertension in later life.

    Delarbeid
    1. Hydronephrosis causes salt-sensitive hypertension in rats
    Åpne denne publikasjonen i ny fane eller vindu >>Hydronephrosis causes salt-sensitive hypertension in rats
    Vise andre…
    2006 (engelsk)Inngår i: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 24, nr 7, s. 1437-1443Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    BACKGROUND: Hypertension is a common disease in the Western world and approximately 5% of all cases are secondary to kidney malfunction. It is not clear whether unilateral hydronephrosis due to partial obstruction affects blood pressure. AIM: The aim of this study was to determine whether hypertension develops and to investigate the effects of different salt diets on the blood pressure in hydronephrotic animals. METHODS: Unilateral partial ureteral obstruction was created in 3-week-old Sprague-Dawley rats. A telemetric device was implanted 4-6 weeks later and blood pressure was measured on normal, low- and high-salt diets. Plasma samples were collected on all diets for renin analysis. RESULTS: All hydronephrotic animals developed hypertension that correlated to the degree of hydronephrosis. The blood pressure increased slowly with time and was salt sensitive. In severe hydronephrosis, blood pressure increased from 118 ± 5 mmHg on low salt to 140 ± 6 mmHg on high salt intake, compared to control levels of 82 ± 2 and 84 ± 2 mmHg, respectively. Plasma renin concentration was increased in the hydronephrotic group of animals compared to controls on all diets, but the difference was only significant on a normal salt diet, 165 ± 15 versus 86 ± 12 μGU/ml respectively. In animals with severe hydronephrosis the plasma renin levels were lower, and the changes less, than in those with mild and moderate hydronephrosis. CONCLUSION: This study demonstrates the presence of a salt-sensitive hypertension in hydronephrosis. A systemic effect of the renin-angiotensin system alone cannot be responsible for the hypertension.

    Emneord
    Hydronephrosis, Hypertension, Nitric oxide, Oxidative stress, Partial ureteral obstruction, Renin, Salt sensitivity
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-96931 (URN)10.1097/01.hjh.0000234126.78766.00 (DOI)000239327900030 ()16794495 (PubMedID)
    Tilgjengelig fra: 2008-03-28 Laget: 2008-03-28 Sist oppdatert: 2017-12-14bibliografisk kontrollert
    2. Relief of chronic partial ureteral obstruction attenuates salt-sensitive hypertension in rats
    Åpne denne publikasjonen i ny fane eller vindu >>Relief of chronic partial ureteral obstruction attenuates salt-sensitive hypertension in rats
    2007 (engelsk)Inngår i: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 189, nr 1, s. 67-75Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Aim: The incidence of hydronephrosis due to ureteropelvic junction obstruction is approx. 0.5%. During the last decade, the management of non-symptomatic hydronephrosis has become much more conservative, but the long-term physiological consequences of this policy are not clear. Previously, we have shown that animals with chronic partial unilateral ureteral obstruction develop salt-sensitive hypertension. In this study, the effects of ipsilateral and contralateral nephrectomy and ureterovesicostomy on blood pressure were studied in hydronephrotic animals.

    Methods: Partial unilateral ureteral obstruction was created in 3-week-old male Sprague–Dawley rats and blood pressure was measured telemetrically 4–6 weeks later during a normal and high salt diet before and after uninephrectomy or ureterovesicostomy. Plasma samples for renin assay were collected during both diets before and after ipsilateral nephrectomy.

    Results: All hydronephrotic animals developed salt-sensitive hypertension, of different degrees. Before nephrectomy the plasma renin concentration was significantly higher in the hydronephrotic animals than in controls (160 ± 15 μGU mL−1 vs. 96 ± 12 μGU mL−1, respectively), but after the ipsilateral nephrectomy no differences were found between the groups. In the hydronephrotic animals both ipsilateral nephrectomy and ureterovesicostomy reduced the blood pressure and salt-sensitivity but the former still differed significantly from the controls. In contralaterally, nephrectomized hydronephrotic animals the salt-sensitive hypertension became more pronounced.

    Conclusion: Hydronephrosis in rats causes salt-sensitive hypertension that can be markedly reduced by removing the hydronephrotic kidney or relieving the obstruction by ureterovesicostomy. The mechanisms appear to be intrarenal and primarily located in the diseased kidney, but a secondary mechanism is also present.

    Emneord
    hydronephrosis, nephrectomy, partial ureteral obstruction, renin, salt-sensitive hypertension, ureterovesicostomy
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-96932 (URN)10.1111/j.1748-1716.2006.01625.x (DOI)000243440900007 ()17280558 (PubMedID)
    Tilgjengelig fra: 2008-03-28 Laget: 2008-03-28 Sist oppdatert: 2017-12-14bibliografisk kontrollert
    3. Hydronephrosis causes salt-sensitive hypertension and impaired renal concentrating ability in mice
    Åpne denne publikasjonen i ny fane eller vindu >>Hydronephrosis causes salt-sensitive hypertension and impaired renal concentrating ability in mice
    Vise andre…
    2007 (engelsk)Inngår i: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 189, nr 3, s. 293-301Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Aim: Hypertension is a common disease in the industrialized world and approximately 5% of all cases are secondary to kidney malfunction. We have recently shown that hydronephrosis due to partial unilateral ureteral obstruction (PUUO) causes salt-sensitive hypertension in rats. The mechanisms are still unclear, but appear to be intrarenal and primarily located to the diseased kidney. In the present study, we have developed a model for PUUO to study if hydronephrotic mice develop salt-sensitive hypertension.

    Methods: PUUO was created in 3-week-old mice (C57bl/6J). Blood pressure and heart rate were measured telemetrically in adult animals on normal and high salt diets. Metabolism cages were used to study the renal excretion of electrolytes and water. Plasma samples for renin analysis were collected and renal histological changes were evaluated.

    Results: All hydronephrotic animals developed salt-sensitive hypertension that correlated to the degree of hydronephrosis. In hydronephrotic animals, blood pressure increased from 114 ± 1 mmHg on normal salt diet to 120 ± 2 mmHg on high salt diet, compared with 103 ± 1 to 104 ± 1 in controls. Hydronephrotic animals showed increased diuresis and reduced ability to regulate electrolyte concentration. No differences in plasma renin concentration were found between the groups. The parenchymal weight and glomerular area of contralateral kidneys were significantly increased in the hydronephrotic animals. Histopathology of the hydronephrotic kidneys displayed areas with fibrosis, inflammation and glomerular changes.

    Conclusion: This study provides a model for PUUO in mice and demonstrates the presence of salt-sensitive hypertension and an impaired renal concentrating ability in mice which has not been described before.

    Emneord
    hydronephrosis, hypertension, nitric oxide, oxidative stress, partial ureteral obstruction, renin, salt sensitivity, telemetry
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-96933 (URN)10.1111/j.1748-1716.2006.01637.x (DOI)000244226300008 ()17305709 (PubMedID)
    Tilgjengelig fra: 2008-03-28 Laget: 2008-03-28 Sist oppdatert: 2017-12-14bibliografisk kontrollert
    4. Role of nitric oxide deficiency in the development of hypertension in hydronephrotic animals
    Åpne denne publikasjonen i ny fane eller vindu >>Role of nitric oxide deficiency in the development of hypertension in hydronephrotic animals
    Vise andre…
    2008 (engelsk)Inngår i: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 294, nr 2, s. 362-370Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Hydronephrotic animals develop renal injury and hypertension, which is associated with an abnormal tubuloglomerular feedback (TGF). The TGF sensitivity is coupled to nitric oxide (NO) in the macula densa. The involvement of reduced NO availability in the development of hypertension in hydronephrosis was investigated. Hydronephrosis was induced by ureteral obstruction in young rats. Blood pressure and renal excretion were measured in adulthood, under different sodium conditions, and before and after chronic administration of either N-G- nitro-L-arginine methyl ester (L-NAME) or L-arginine. Blood samples for ADMA, SDMA, and L-arginine analysis were taken and the renal tissue was used for histology and determination of NO synthase (NOS) proteins. TGF characteristics were determined by stop-flow pressure technique before and after administration of 7-nitroindazole (7-NI) or L-arginine. Hydronephrotic animals developed salt-sensitive hypertension, which was associated with pressure natriuresis and diuresis. The blood pressure response to L-NAME was attenuated and L-arginine supplementation decreased blood pressure in hydronephrotic animals, but not in the controls. Under control conditions, reactivity and sensitivity of the TGF response were greater in the hydronephrotic group. 7-NI administration increased TGF reactivity and sensitivity in control animals, whereas, in hydronephrotic animals, neuronal NOS (nNOS) inhibition had no effect. L-Arginine attenuated TGF response more in hydronephrotic kidneys than in controls. The hydronephrotic animals displayed various degrees of histopathological changes. ADMA and SDMA levels were higher and the renal expressions of nNOS and endothelial NOS proteins were lower in animals with hydronephrosis. Reduced NO availability in the diseased kidney in hydronephrosis, and subsequent resetting of the TGF mechanism, plays an important role in the development of hypertension.

    Emneord
    ADMA, tubuloglomerular feedback, L-arginine, L-NAME, telemetry, blood pressure
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-96934 (URN)10.1152/ajprenal.00410.2007 (DOI)000252744300010 ()
    Tilgjengelig fra: 2008-03-28 Laget: 2008-03-28 Sist oppdatert: 2017-12-14
  • 264.
    Carlström, Mattias
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Hydronephrosis and hypertension2006Licentiatavhandling, monografi (Annet vitenskapelig)
  • 265.
    Carlström, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Response to Sex of the Animal Impacts Responses to Angiotensin II, Oxidative Stress Levels, and Nitric Oxide Bioavailability2011Inngår i: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 57, nr 5, s. E19-E19Artikkel i tidsskrift (Fagfellevurdert)
  • 266.
    Carlström, Mattias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Brown, Russell D
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Sällström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Larsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Zilmer, Mihkel
    Zabihi, Sheller
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Eriksson, Ulf J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Persson, A Erik G
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    SOD1-Deficiency Causes Salt-Sensitivity and Aggravates Hypertension in Hydronephrosis2009Inngår i: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 297, nr 1, s. R82-R92Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Hydronephrosis causes renal dysfunction and salt-sensitive hypertension, which is associated with NO-deficiency and abnormal tubuloglomerular feedback (TGF) response. We investigated the role of oxidative stress for salt-sensitivity and for hypertension in hydronephrosis. Methods: Hydronephrosis was induced in SOD1-transgenic (SOD1-tg), SOD1-deficient (SOD1-ko) and wild-type mice and in rats. In mice, telemetric measurements were performed during normal (0.7% NaCl) and high sodium (4% NaCl) diets and with chronic Tempol supplementation. 8-iso-prostaglandin-F2alpha (F2-IsoPs) and protein excretion profiles and histology were investigated. The acute effects of Tempol on blood pressure and TGF were studied in rats. Results: In hydronephrosis, wild-type mice developed salt-sensitive hypertension (114+/-1 to 120+/-2 mmHg) which was augmented in SOD1-ko (125+/-3 to 135+/-4 mmHg), but abolished in SOD1-tg (109+/-3 to 108+/-3 mmHg). SOD1-ko controls displayed salt-sensitive blood pressure (108+/-1 to 115+/-2 mmHg), which was not found in wild-types or SOD1-tg. Chronic Tempol treatment reduced blood pressure in SOD1-ko controls (-7 mmHg) and in hydronephrotic wild-types (-8 mmHg) and SOD1-ko mice (-16 mmHg), but had no effect on blood pressure in wild-type or SOD1-tg controls. SOD1-ko controls and hydronephrotic wild-type and SOD1-ko mice exhibited increased fluid excretion associated with increased F2-IsoPs and protein excretion. The renal histopathological changes found in hydronephrotic wild-types were augmented in SOD1-ko and diminished in SOD-tg mice. Tempol attenuated blood pressure and normalized TGF response in hydronephrosis (DeltaPSF: 15.2+/-1.2 to 9.1+/-0.6 mmHg, TP: 14.3+/-0.8 to 19.7+/-1.4 nl/min). Conclusion: Oxidative stress due to SOD1-deficiency causes salt-sensitivity and plays a pivotal role for the development of hypertension in hydronephrosis. Increased superoxide formation may enhance TGF response and thereby contribute to hypertension.

  • 267.
    Carlström, Mattias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Brown, Russell D.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Yang, T.
    Hezel, M.
    Larsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Scheffer, P. G.
    Teerlink, T.
    Lundberg, J. O.
    Persson, A. Erik G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    L-arginine or tempol supplementation improves renal and cardiovascular function in rats with reduced renal mass and chronic high salt intake2013Inngår i: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 207, nr 4, s. 732-741Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aim Early life reduction in nephron number and chronic high salt intake cause development of renal and cardiovascular disease, which has been associated with oxidative stress and nitric oxide (NO) deficiency. We investigated the hypothesis that interventions stimulating NO signalling or reducing oxidative stress may restore renal autoregulation, attenuate hypertension and reduce renal and cardiovascular injuries following reduction in renal mass and chronic high salt intake. Methods Male SpragueDawley rats were uninephrectomized (UNX) or sham-operated at 3weeks of age and given either a normal-salt (NS) or high-salt (HS) diet. Effects on renal and cardiovascular functions were assessed in rats supplemented with substrate for NO synthase (L-Arg) or a superoxide dismutase mimetic (Tempol). Results Rats with UNX+HS developed hypertension and displayed increased renal NADPH oxidase activity, elevated levels of oxidative stress markers in plasma and urine, and reduced cGMP in plasma. Histological analysis showed signs of cardiac and renal inflammation and fibrosis. These changes were linked with abnormal renal autoregulation, measured as a stronger tubuloglomerular feedback (TGF) response. Simultaneous treatment with L-Arg or Tempol restored cGMP levels in plasma and increased markers of NO signalling in the kidney. This was associated with normalized TGF responses, attenuated hypertension and reduced signs of histopathological changes in the kidney and in the heart. Conclusion Reduction in nephron number during early life followed by chronic HS intake is associated with oxidative stress, impaired renal autoregulation and development of hypertension. Treatment strategies that increase NO bioavailability, or reduce levels of reactive oxygen species, were proven beneficial in this model of renal and cardiovascular disease.

  • 268.
    Carlström, Mattias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Brown, Russell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Edlund, Jenny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Sällström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Larsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Teerlink, Tom
    Palm, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Wåhlin, Nils
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Persson, A. Erik G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Role of nitric oxide deficiency in the development of hypertension in hydronephrotic animals2008Inngår i: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 294, nr 2, s. 362-370Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hydronephrotic animals develop renal injury and hypertension, which is associated with an abnormal tubuloglomerular feedback (TGF). The TGF sensitivity is coupled to nitric oxide (NO) in the macula densa. The involvement of reduced NO availability in the development of hypertension in hydronephrosis was investigated. Hydronephrosis was induced by ureteral obstruction in young rats. Blood pressure and renal excretion were measured in adulthood, under different sodium conditions, and before and after chronic administration of either N-G- nitro-L-arginine methyl ester (L-NAME) or L-arginine. Blood samples for ADMA, SDMA, and L-arginine analysis were taken and the renal tissue was used for histology and determination of NO synthase (NOS) proteins. TGF characteristics were determined by stop-flow pressure technique before and after administration of 7-nitroindazole (7-NI) or L-arginine. Hydronephrotic animals developed salt-sensitive hypertension, which was associated with pressure natriuresis and diuresis. The blood pressure response to L-NAME was attenuated and L-arginine supplementation decreased blood pressure in hydronephrotic animals, but not in the controls. Under control conditions, reactivity and sensitivity of the TGF response were greater in the hydronephrotic group. 7-NI administration increased TGF reactivity and sensitivity in control animals, whereas, in hydronephrotic animals, neuronal NOS (nNOS) inhibition had no effect. L-Arginine attenuated TGF response more in hydronephrotic kidneys than in controls. The hydronephrotic animals displayed various degrees of histopathological changes. ADMA and SDMA levels were higher and the renal expressions of nNOS and endothelial NOS proteins were lower in animals with hydronephrosis. Reduced NO availability in the diseased kidney in hydronephrosis, and subsequent resetting of the TGF mechanism, plays an important role in the development of hypertension.

  • 269.
    Carlström, Mattias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Lai, En Yin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Ma, Zufu
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Patzak, Andreas
    Brown, Russell D.
    Department of Physiology, Monash University, Monash, Australia .
    Persson, A. Erik G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Role of NOX2 in the regulation of afferent arteriole responsiveness2009Inngår i: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 296, nr 1, s. R72-R79Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    NADPH oxidases (NOX) are the major source of reactive oxygen species (ROS) in the vasculature and contribute to the control of renal perfusion. The role of NOX2 in the regulation of blood pressure and afferent arteriole responsiveness was investigated in NOX2(-/-) and wild-type mice. Arteriole constrictions to ANG II (10(-14)-10(-6) mol/l) were weaker in NOX2(-/-) compared with wild types. N(omega)-nitro-l-arginine methyl ester (l-NAME; 10(-4) mol/l) treatment reduced basal diameters significantly more in NOX2(-/-) (-18%) than in wild types (-6%) and augmented ANG II responses. Adenosine (10(-11)-10(-4) mol/l) constricted arterioles of wild types but not of NOX2(-/-). However, simultaneous inhibition of adenosine type-2 receptors induced vasoconstriction, which was stronger in NOX2(-/-). Adenosine (10(-8) mol/l) enhanced the ANG II response in wild type, but not in NOX2(-/-). This sensitizing effect by adenosine was abolished by apocynin. Chronic ANG II pretreatment (14 days) did not change the ANG II responses in NOX2(-/-), but strengthened the response in wild types. ANG II pretreatment augmented the l-NAME response in NOX2(-/-) (-33%), but not in wild types. Simultaneous application of l-NAME and ANG II caused a stronger constriction in the NOX2(-/-) (-64%) than in wild types (-46%). Basal blood pressures were similar in both genotypes, however, chronic ANG II infusion elevated blood pressure to a greater extent in wild-type (15 +/- 1%) than in NOX2(-/-) (8 +/- 1%) mice. In conclusion, NOX2 plays an important role in the control of afferent arteriole tone and is involved in the contractile responses to ANG II and/or adenosine. NOX2 can be activated by elevated ANG II and may play an important role in ANG II-induced hypertension. NOX2-derived ROS scavenges nitric oxide, causing subsequent nitric oxide-deficiency.

  • 270.
    Carlström, Mattias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Lai, En Yin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Ma, Zufu
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Steege, Andreas
    Patzak, Andreas
    Eriksson, Ulf J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Lundberg, Jon O.
    Wilcox, Christopher S.
    Persson, A. Erik G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Superoxide Dismutase 1 Limits Renal Microvascular Remodeling and Attenuates Arteriole and Blood Pressure Responses to Angiotensin II via Modulation of Nitric Oxide Bioavailability2010Inngår i: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 56, nr 5, s. 907-913Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Oxidative stress is associated with vascular remodeling and increased preglomerular resistance that are both implicated in the pathogenesis of renal and cardiovascular disease. Angiotensin II induces superoxide production, which is metabolized by superoxide dismutase (SOD) or scavenged by NO. We investigated the hypothesis that SOD1 regulates renal microvascular remodeling, blood pressure, and arteriolar responsiveness and sensitivity to angiotensin II using SOD1-transgenic (SOD1-tg) and SOD1-knockout (SOD1-ko) mice. Blood pressure, measured telemetrically, rose more abruptly during prolonged angiotensin II infusion in SOD1-ko mice. The afferent arteriole media: lumen ratios were reduced in SOD1-tg and increased in SOD1-ko mice. Afferent arterioles from nontreated wild types had graded contraction to angiotensin II (sensitivity: 10(-9) mol/L; responsiveness: 40%). Angiotensin II contractions were less sensitive (10(-8) mol/L) and responsive (14%) in SOD1-tg but more sensitive (10(-13) mol/L) and responsive (89%) in SOD1-ko mice. Arterioles from SOD1-ko had 4-fold increased superoxide formation with angiotensin II at 10(-9) mol/L. N-G-nitro-L-arginine methyl ester reduced arteriole diameter of SOD1-tg and enhanced angiotensin II sensitivity and responsiveness of wild-type and SOD1-tg mice to the level of SOD1-ko mice. SOD mimetic treatment with Tempol increased arteriole diameter and normalized the enhanced sensitivity and responsiveness to angiotensin II of SOD1-ko mice but did not affect wild-type or SOD1-tg mice. Neither SOD1 deficiency nor overexpression was associated with changes in nitrate/nitrite excretion or renal mRNA expression of NO synthase, NADPH oxidase, or SOD2/SOD3 isoforms and angiotensin II receptors. In conclusion, SOD1 limits afferent arteriole remodeling and reduces sensitivity and responsiveness to angiotensin II by reducing superoxide and maintaining NO bioavailability. This may prevent an early and exaggerated blood pressure response to angiotensin II.

  • 271.
    Carlström, Mattias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Lai, En Yin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Steege, Andreas
    Sendeski, Mauricio
    Ma, Zufu
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Zabihi, Sheller
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Eriksson, Ulf J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Patzak, Andreas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Persson, A. Erik G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Nitric oxide deficiency and increased adenosine response of afferent arterioles in hydronephrotic mice with hypertension2008Inngår i: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 51, nr 5, s. 1386-1392Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Afferent arterioles were used to investigate the role of adenosine, angiotensin II, NO, and reactive oxygen species in the pathogenesis of increased tubuloglomerular feedback response in hydronephrosis. Hydronephrosis was induced in wild-type mice, superoxide dismutase-1 overexpressed mice (superoxide-dismutase-1 transgenic), and deficient mice (superoxide dismutase-1 knockout). Isotonic contractions in isolated perfused arterioles and mRNA expression of NO synthase isoforms, adenosine, and angiotensin II receptors were measured. In wild-type mice, N(G)-nitro-L-arginine methyl ester (L-NAME) did not change the basal arteriolar diameter of hydronephrotic kidneys (-6%) but reduced it in control (-12%) and contralateral arterioles (-43%). Angiotensin II mediated a weaker maximum contraction of hydronephrotic arterioles (-18%) than in control (-42%) and contralateral arterioles (-49%). The maximum adenosine-induced constriction was stronger in hydronephrotic (-19%) compared with control (-8%) and contralateral kidneys (+/-0%). The response to angiotensin II became stronger in the presence of adenosine in hydronephrotic kidneys and attenuated in contralateral arterioles. L-NAME increased angiotensin II responses of all of the groups but less in hydronephrotic kidneys. The mRNA expression of endothelial NO synthase and inducible NO synthase was upregulated in the hydronephrotic arterioles. No differences were found for adenosine or angiotensin II receptors. In superoxide dismutase-1 transgenic mice, strong but similar L-NAME response (-40%) was observed for all of the groups. This response was totally abolished in arterioles of hydronephrotic superoxide dismutase-1 knockout mice. In conclusion, hydronephrosis is associated with changes in the arteriolar reactivity of both hydronephrotic and contralateral kidneys. Increased oxidative stress, reduced NO availability, and stronger reactivity to adenosine of the hydronephrotic kidney may contribute to the enhanced tubuloglomerular feedback responsiveness in hydronephrosis and be involved in the development of hypertension.

  • 272.
    Carlström, Mattias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Larsen, Filip J.
    Nystrom, Thomas
    Hezel, Michael
    Borniquel, Sara
    Weitzberg, Eddie
    Lundberg, Jon O.
    Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice2010Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 107, nr 41, s. 17716-17720Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The metabolic syndrome is a clustering of risk factors of metabolic origin that increase the risk for cardiovascular disease and type 2 diabetes. A proposed central event in metabolic syndrome is a decrease in the amount of bioavailable nitric oxide (NO) from endothelial NO synthase (eNOS). Recently, an alternative pathway for NO formation in mammals was described where inorganic nitrate, a supposedly inert NO oxidation product and unwanted dietary constituent, is serially reduced to nitrite and then NO and other bioactive nitrogen oxides. Here we show that several features of metabolic syndrome that develop in eNOS-deficient mice can be reversed by dietary supplementation with sodium nitrate, in amounts similar to those derived from eNOS under normal conditions. In humans, this dose corresponds to a rich intake of vegetables, the dominant dietary nitrate source. Nitrate administration increased tissue and plasma levels of bioactive nitrogen oxides. Moreover, chronic nitrate treatment reduced visceral fat accumulation and circulating levels of triglycerides and reversed the prediabetic phenotype in these animals. In rats, chronic nitrate treatment reduced blood pressure and this effect was also present during NOS inhibition. Our results show that dietary nitrate fuels a nitrate-nitrite-NO pathway that can partly compensate for disturbances in endogenous NO generation from eNOS. These findings may have implications for novel nutrition-based preventive and therapeutic strategies against cardiovascular disease and type 2 diabetes.

  • 273.
    Carlström, Mattias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Larsen, Filip J.
    Nyström, Thomas
    Hezel, Michael
    Borniquel, Sara
    Weitzberg, Eddie
    Lundberg, Jon O.
    Therapeutical Role of Dietary Inorganic Nitrate in eNOS-deficient mice with Metabolic Syndrome2010Inngår i: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 49, s. S36-S36Artikkel i tidsskrift (Annet vitenskapelig)
  • 274.
    Carlström, Mattias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden..
    Liu, Ming
    Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden..
    Yang, Ting
    Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden..
    Zollbrecht, Christa
    Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden..
    Huang, Liyue
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden..
    Peleli, Maria
    Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden..
    Borniquel, Sara
    Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden..
    Kishikawa, Hiroaki
    Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden..
    Hezel, Michael
    Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden..
    Persson, A. Erik G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Weitzberg, Eddie
    Karolinska Inst, Div Anesthesiol & Intens Care, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Lundberg, Jon O.
    Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden..
    Cross-talk Between Nitrate-Nitrite-NO and NO Synthase Pathways in Control of Vascular NO Homeostasis2015Inngår i: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 23, nr 4, s. 295-306Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims: Inorganic nitrate and nitrite from endogenous and dietary sources have emerged as alternative substrates for nitric oxide (NO) formation in addition to the classic L-arginine NO synthase (NOS)-dependent pathway. Here, we investigated a potential cross-talk between these two pathways in the regulation of vascular function. Results: Long-term dietary supplementation with sodium nitrate (0.1 and 1mmol kg(-1) day(-1)) in rats caused a reversible dose-dependent reduction in phosphorylated endothelial NOS (eNOS) (Ser1177) in aorta and a concomitant increase in phosphorylation at Thr495. Moreover, eNOS-dependent vascular responses were attenuated in vessels harvested from nitrate-treated mice or when nitrite was acutely added to control vessels. The citrulline-to-arginine ratio in plasma, as a measure of eNOS activity, was reduced in nitrate-treated rodents. Telemetry measurements revealed that a low dietary nitrate dose reduced blood pressure, whereas a higher dose was associated with a paradoxical elevation. Finally, plasma cyclic guanosine monophosphate increased in mice that were treated with a low dietary nitrate dose and decreased with a higher dose. Innovation and Conclusions: These results demonstrate the existence of a cross-talk between the nitrate-nitrite-NO pathway and the NOS-dependent pathway in control of vascular NO homeostasis. Antioxid. Redox Signal. 23, 295-306.

  • 275.
    Carlström, Mattias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Persson, A. Erik G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Important role of NAD(P)H oxidase 2 in the regulation of the tubuloglomerular feedback2009Inngår i: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 53, nr 3, s. 456-457Artikkel i tidsskrift (Fagfellevurdert)
  • 276.
    Carlström, Mattias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Persson, Anders Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Larsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Hezel, Michael
    Scheffer, Peter G.
    Teerlink, Tom
    Weitzberg, Eddie
    Lundberg, Jon O.
    Dietary nitrate attenuates oxidative stress, prevents cardiac and renal injuries, and reduces blood pressure in salt-induced hypertension2011Inngår i: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, Vol. 89, nr 3, s. 574-585Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims Reduced bioavailability of endogenous nitric oxide (NO) is a central pathophysiological event in hypertension and other cardiovascular diseases. Recently, it was demonstrated that inorganic nitrate from dietary sources is converted in vivo to form nitrite, NO, and other bioactive nitrogen oxides. We tested the hypothesis that dietary inorganic nitrate supplementation may have therapeutic effects in a model of renal and cardiovascular disease.

    Methods and results Sprague-Dawley rats subjected to unilateral nephrectomy and chronic high-salt diet from 3 weeks of age developed hypertension, cardiac hypertrophy and fibrosis, proteinuria, and histological as well as biochemical signs of renal damage and oxidative stress. Simultaneous nitrate treatment (0.1 or 1 mmol nitrate kg(-1) day(-1)), with the lower dose resembling the nitrate content of a diet rich in vegetables, attenuated hypertension dose-dependently with no signs of tolerance. Nitrate treatment almost completely prevented proteinuria and histological signs of renal injury, and the cardiac hypertrophy and fibrosis were attenuated. Mechanistically, dietary nitrate restored the tissue levels of bioactive nitrogen oxides and reduced the levels of oxidative stress markers in plasma (malondialdehyde) and urine (Class VI F2-isoprostanes and 8-hydroxy-2-deoxyguanosine). In addition, the increased circulating and urinary levels of dimethylarginines (ADMA and SDMA) in the hypertensive rats were normalized by nitrate supplementation.

    Conclusion Dietary inorganic nitrate is strongly protective in this model of renal and cardiovascular disease. Future studies will reveal if nitrate contributes to the well-known cardioprotective effects of a diet rich in vegetables.

  • 277.
    Carlström, Mattias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Persson, Erik G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Larsson, Erik
    Uppsala universitet.
    Hezel, Michael
    Scheffer, Peter
    Teerlink, Tom
    Weitzberg, Eddie
    Lundberg, Jon O.
    Dietary Inorganic Nitrate Attenuates Oxidative Stress and Hypertension, and Prevents Cardiorenal injury in a Model of Renal and Cardiovascular Disease2010Inngår i: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 49, s. S16-S16Artikkel i tidsskrift (Annet vitenskapelig)
  • 278.
    Carlström, Mattias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Sällström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Skott, Ole
    Larsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Persson, Erik G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Uninephrectomy in Young Age or Chronic Salt Loading Causes Salt-Sensitive Hypertension in Adult Rats2007Inngår i: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 49, nr 6, s. 1342-1350Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The importance of nephron endowment and salt intake for the development of hypertension is under debate. The present study was designed to investigate whether reduced nephron number, after completion of nephrogenesis, or chronic salt loading causes renal injury and salt-sensitive hypertension in adulthood. Rats were operated at 3 weeks of age (after completed nephrogenesis) and then subjected to either normal or high-salt diets for 6 to 8 weeks. Four different experimental groups were used: sham-operated animals raised with normal-salt diet (controls) or high-salt diet (HS) and uninephrectomized animals raised with normal-salt diet (UNX) or high-salt diet (UNX+HS). In the adult animals, renal and cardiovascular functions were evaluated and blood pressure recorded telemetrically under different sodium conditions (normal, high, and low). Hypertension was present in UNX+HS (122±9 mm Hg), UNX (101±3 mm Hg), and HS (96± 1 mm Hg) groups on normal-salt diets compared with the controls (84±2 mm Hg), and the blood pressure was salt sensitive (high- versus normal-salt diet; 23±3, 9±2, 7±2, and 1±1 mm Hg, respectively). The hypertensive groups (UNX+HS, UNX, and HS) had increased diuresis and reduced ability to concentrate urine. The glomerular filtration rate (milliliters per minute) in anesthetized rats was reduced in the UNX+HS (2.36±0.30) and UNX animals (2.00±0.31) compared with both HS animals (3.55±0.45) and controls (3.01±0.35). Hypertensive groups displayed reduced plasma renin concentrations during high sodium conditions and hypertrophic kidneys and hearts with various degrees of histopathologic changes. In conclusion, at a young age after completed nephrogenesis, uninephrectomy or chronic salt loading causes renal and cardiovascular injury with salt-sensitive hypertension.

  • 279.
    Carlström, Mattias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Sällström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Skott, Ole
    Larsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Wåhlin, Nils
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Persson, A. Erik G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Hydronephrosis causes salt-sensitive hypertension and impaired renal concentrating ability in mice2007Inngår i: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 189, nr 3, s. 293-301Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aim: Hypertension is a common disease in the industrialized world and approximately 5% of all cases are secondary to kidney malfunction. We have recently shown that hydronephrosis due to partial unilateral ureteral obstruction (PUUO) causes salt-sensitive hypertension in rats. The mechanisms are still unclear, but appear to be intrarenal and primarily located to the diseased kidney. In the present study, we have developed a model for PUUO to study if hydronephrotic mice develop salt-sensitive hypertension.

    Methods: PUUO was created in 3-week-old mice (C57bl/6J). Blood pressure and heart rate were measured telemetrically in adult animals on normal and high salt diets. Metabolism cages were used to study the renal excretion of electrolytes and water. Plasma samples for renin analysis were collected and renal histological changes were evaluated.

    Results: All hydronephrotic animals developed salt-sensitive hypertension that correlated to the degree of hydronephrosis. In hydronephrotic animals, blood pressure increased from 114 ± 1 mmHg on normal salt diet to 120 ± 2 mmHg on high salt diet, compared with 103 ± 1 to 104 ± 1 in controls. Hydronephrotic animals showed increased diuresis and reduced ability to regulate electrolyte concentration. No differences in plasma renin concentration were found between the groups. The parenchymal weight and glomerular area of contralateral kidneys were significantly increased in the hydronephrotic animals. Histopathology of the hydronephrotic kidneys displayed areas with fibrosis, inflammation and glomerular changes.

    Conclusion: This study provides a model for PUUO in mice and demonstrates the presence of salt-sensitive hypertension and an impaired renal concentrating ability in mice which has not been described before.

  • 280.
    Carlström, Mattias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Wentzel, Parri
    Skott, Ole
    Persson, A. Erik G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Eriksson, Ulf J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Angiogenesis inhibition causes hypertension and placental dysfunction in a rat model of preeclampsia2009Inngår i: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 27, nr 4, s. 829-837Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background Preeclampsia is a serious pregnancy complication, accompanied by increased maternal and fetal morbidity. Different models have been used to study preeclampsia, but none of these display all the key features of the disease. Method We investigated the effects on maternal blood pressure and fetal outcome exerted by the angiogenesis inhibitor Suramin (1100 mg/kg i.p.) during early placentation. Blood pressure and heart rate were measured continuously with telemetry in Sprague - Dawley rats of four experimental groups: nonpregnant controls, Suramin-treated nonpregnant rats, pregnant controls and pregnant Suramin-treated rats. Blood samples were collected before pregnancy and at gestational day 20 for analysis of renin and sFIt-1. The fetal and placental morphology were evaluated after caesarian section on gestational day 20. Results The blood pressure of the pregnant Suramin-treated rats successively increased during pregnancy and differed by 17 mmHg at gestational day 20 compared with the pregnant control rats. In the pregnant Suramin-treated rats group, the renin levels increased (+122%) and the sFIt-1 levels decreased (-58%) during pregnancy. The pregnant Suramin-treated fetuses and placentae were smaller (2.8 g and 0.51 g) than the pregnant controls rats' fetuses and placentae (3.5g and 0.56g). Resorptions tended to be higher in the pregnant Suramin-treated rat litters compared with the pregnant control rat litters (P = 0.08). The area of the maternal blood vessels in the mesometrial triangle was smaller in the pregnant Suramin-treated rats group than in the pregnant control rats group. Conclusion The inhibition of uterine angiogenesis increases maternal blood pressure and compromises fetal and placental development. Placental hypoxia and subsequent activation of the renin-angiotensin system may play an important role for the hypertension. J Hypertens 27:829-837 (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.

  • 281.
    Carlström, Mattias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Wåhlin, Nils
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Skott, Ole
    Persson, A. Erik G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Relief of chronic partial ureteral obstruction attenuates salt-sensitive hypertension in rats2007Inngår i: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 189, nr 1, s. 67-75Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aim: The incidence of hydronephrosis due to ureteropelvic junction obstruction is approx. 0.5%. During the last decade, the management of non-symptomatic hydronephrosis has become much more conservative, but the long-term physiological consequences of this policy are not clear. Previously, we have shown that animals with chronic partial unilateral ureteral obstruction develop salt-sensitive hypertension. In this study, the effects of ipsilateral and contralateral nephrectomy and ureterovesicostomy on blood pressure were studied in hydronephrotic animals.

    Methods: Partial unilateral ureteral obstruction was created in 3-week-old male Sprague–Dawley rats and blood pressure was measured telemetrically 4–6 weeks later during a normal and high salt diet before and after uninephrectomy or ureterovesicostomy. Plasma samples for renin assay were collected during both diets before and after ipsilateral nephrectomy.

    Results: All hydronephrotic animals developed salt-sensitive hypertension, of different degrees. Before nephrectomy the plasma renin concentration was significantly higher in the hydronephrotic animals than in controls (160 ± 15 μGU mL−1 vs. 96 ± 12 μGU mL−1, respectively), but after the ipsilateral nephrectomy no differences were found between the groups. In the hydronephrotic animals both ipsilateral nephrectomy and ureterovesicostomy reduced the blood pressure and salt-sensitivity but the former still differed significantly from the controls. In contralaterally, nephrectomized hydronephrotic animals the salt-sensitive hypertension became more pronounced.

    Conclusion: Hydronephrosis in rats causes salt-sensitive hypertension that can be markedly reduced by removing the hydronephrotic kidney or relieving the obstruction by ureterovesicostomy. The mechanisms appear to be intrarenal and primarily located in the diseased kidney, but a secondary mechanism is also present.

  • 282.
    Carlström, Mattias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Wåhlin, Nils
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Sällström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Skott, Ole
    Brown, Russell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Persson, A. Erik G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Hydronephrosis causes salt-sensitive hypertension in rats2006Inngår i: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 24, nr 7, s. 1437-1443Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Hypertension is a common disease in the Western world and approximately 5% of all cases are secondary to kidney malfunction. It is not clear whether unilateral hydronephrosis due to partial obstruction affects blood pressure. AIM: The aim of this study was to determine whether hypertension develops and to investigate the effects of different salt diets on the blood pressure in hydronephrotic animals. METHODS: Unilateral partial ureteral obstruction was created in 3-week-old Sprague-Dawley rats. A telemetric device was implanted 4-6 weeks later and blood pressure was measured on normal, low- and high-salt diets. Plasma samples were collected on all diets for renin analysis. RESULTS: All hydronephrotic animals developed hypertension that correlated to the degree of hydronephrosis. The blood pressure increased slowly with time and was salt sensitive. In severe hydronephrosis, blood pressure increased from 118 ± 5 mmHg on low salt to 140 ± 6 mmHg on high salt intake, compared to control levels of 82 ± 2 and 84 ± 2 mmHg, respectively. Plasma renin concentration was increased in the hydronephrotic group of animals compared to controls on all diets, but the difference was only significant on a normal salt diet, 165 ± 15 versus 86 ± 12 μGU/ml respectively. In animals with severe hydronephrosis the plasma renin levels were lower, and the changes less, than in those with mild and moderate hydronephrosis. CONCLUSION: This study demonstrates the presence of a salt-sensitive hypertension in hydronephrosis. A systemic effect of the renin-angiotensin system alone cannot be responsible for the hypertension.

  • 283.
    Carvalho, Carla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    The Role of Kidney Oxygen Homeostasis for the Development of Kidney Disease2019Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The relation between oxygen supply and demand determines tissue oxygen tension (PO2). When intrarenal tissue PO2 decreases, any compensatory increase in oxygen supply via increased renal blood flow is likely to increase glomerular filtration rate. The resulting increased tubular load of electrolytes destined for active transport increases oxygen consumption, thus affecting intrarenal tissue PO2. Consequently, the kidney is particularly sensitive to alterations in oxygen homeostasis and kidney hypoxia is acknowledged as a common pathway to end stage renal disease. Different factors that can affect intrarenal oxygen homeostasis, including alterations in blood pressure and sodium intake dietary or pathologies such as diabetes mellitus, anemia or atherosclerosis. This thesis focuses on understanding how these factors influence kidney oxygen homeostasis.

    Pronounced reduction in sodium intake caused tissue hypoxia in kidney cortex via activation of the renin-angiotensin-aldosterone leading to increased tubular sodium reabsorption. Angiotensin II and aldosterone affect kidney oxygen handling differently. Whereas angiotensin II mainly affects kidney oxygen delivery, aldosterone mainly affects oxygen consumption.

    The hypoxia-inducible factor (HIF) system is a cellular defense mechanism against prolonged hypoxia. Although diabetes causes intrarenal hypoxia, hyperglycemia per se also prevents HIF-activation. Therefore, the effects of type 1 diabetes were evaluated in genetically modified mice with chronic HIF-activation. Diabetic mice with globally increased HIF activity, due to heterozygote prolyl hydroxylase-2 deficiency, displayed reduced mitochondria leak respiration and preserved cortical PO2. Diabetic mice with kidney-specific HIF activation, due to homozygous deficiency of von Hippel-Lindau, developed reduced mitochondria leak respiration and reduced urinary albumin excretion.

    The normal age-related decline in kidney function has been proposed to be due to, at least in part, increased oxidative stress, which can induce mitochondrial leak respiration via activation of uncoupling proteins. Indeed, two-year old mice deficient of uncoupling protein-2 presented with improved mitochondria efficiency and reduced urinary protein excretion.

    Summarizing, the data presented in this thesis provide clear support for potent influence of the renin-angiotensin-aldosterone system, HIF activation and mitochondria function on intrarenal oxygen availability. Maintaining kidney oxygen homeostasis may be a unifying strategy to protect kidney function.

    Delarbeid
    1. Determinants of renal oxygen metabolism during low Na+ diet: effect of angiotensin AT1 and aldosterone receptor blockade
    Åpne denne publikasjonen i ny fane eller vindu >>Determinants of renal oxygen metabolism during low Na+ diet: effect of angiotensin AT1 and aldosterone receptor blockade
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-387381 (URN)
    Tilgjengelig fra: 2019-06-23 Laget: 2019-06-23 Sist oppdatert: 2019-06-23
    2. Activation of hypoxia inducible factor due to reduced prolyl hydroxylase 2 activity prevents renal mitochondria dysfunction and improves cortical oxygenation in type 1 diabetic mice
    Åpne denne publikasjonen i ny fane eller vindu >>Activation of hypoxia inducible factor due to reduced prolyl hydroxylase 2 activity prevents renal mitochondria dysfunction and improves cortical oxygenation in type 1 diabetic mice
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-387385 (URN)
    Tilgjengelig fra: 2019-06-23 Laget: 2019-06-23 Sist oppdatert: 2019-06-23
    3. Hypoxia-inducible factors activation protects mitochondria function and prevents albuminuria in kidney-specific diabetic von Hippel-Lindau deficient mice
    Åpne denne publikasjonen i ny fane eller vindu >>Hypoxia-inducible factors activation protects mitochondria function and prevents albuminuria in kidney-specific diabetic von Hippel-Lindau deficient mice
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-387387 (URN)
    Tilgjengelig fra: 2019-06-23 Laget: 2019-06-23 Sist oppdatert: 2019-06-23
    4. Uncoupling protein 2 mediates age-related mitochondria inefficiency and urinary protein excretion
    Åpne denne publikasjonen i ny fane eller vindu >>Uncoupling protein 2 mediates age-related mitochondria inefficiency and urinary protein excretion
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-387388 (URN)
    Tilgjengelig fra: 2019-06-23 Laget: 2019-06-23 Sist oppdatert: 2019-06-23
  • 284. Carvalho, Carla
    et al.
    Schiffer, Tomas A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Karlsson, Susanne
    Hansell, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Friederich, Malou
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Palm, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Uncoupling protein 2 mediates age-related mitochondria inefficiency and urinary protein excretionManuskript (preprint) (Annet vitenskapelig)
  • 285. Carvalho, Carla
    et al.
    Schiffer, Tomas A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Zheng, Xiao-Wei
    Grünler, Jacob
    Karlsson, Susanne
    Mazzone, Massimiliano
    Carmeliet, Peter
    Hansell, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Catrina, Sergiu-Bogdan
    Friederich, Malou
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Palm, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Hypoxia-inducible factors activation protects mitochondria function and prevents albuminuria in kidney-specific diabetic von Hippel-Lindau deficient miceManuskript (preprint) (Annet vitenskapelig)
  • 286. Carvalho, Carla
    et al.
    Schiffer, Tomas A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Zheng, Xiao-Wei
    Grünler, Jacob
    Karlsson, Susanne
    Mazzone, Massimiliano
    Carmeliet, Peter
    Inagi, Reiko
    Hansell, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Catrina, Sergiu-Bogdan
    Friederich, Malou
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Palm, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Activation of hypoxia inducible factor due to reduced prolyl hydroxylase 2 activity prevents renal mitochondria dysfunction and improves cortical oxygenation in type 1 diabetic miceManuskript (preprint) (Annet vitenskapelig)
  • 287.
    Cat, Aurelie Nguyen Dinh
    et al.
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland..
    Callera, Glaucia E.
    Univ Ottawa, Ottawa Hosp, Res Inst, Kidney Res Ctr, Ottawa, ON, Canada..
    Friederich, Malou
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland.
    Sanchez, Ana
    Univ Complutense, Fac Farm, Dept Fisiol, Madrid, Spain..
    Dulak-Lis, Maria Gabriela
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland..
    Tsiropoulou, Sofia
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland..
    Montezano, Augusto C.
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland..
    He, Ying
    Univ Ottawa, Ottawa Hosp, Res Inst, Kidney Res Ctr, Ottawa, ON, Canada..
    Briones, Ana M.
    Univ Autonoma Madrid, CIBER Enfermedades Cardiovasc, Sch Med, Dept Pharmacol, Madrid, Spain..
    Jaisser, Frederic
    Ctr Rech Cordeliers, INSERM Team 1 1138, Paris, France..
    Touyz, Rhian M.
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland.;Univ Ottawa, Ottawa Hosp, Res Inst, Kidney Res Ctr, Ottawa, ON, Canada..
    Vascular dysfunction in obese diabetic db/db mice involves the interplay between aldosterone/mineralocorticoid receptor and Rho kinase signaling2018Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikkel-id 2952Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Activation of aldosterone/mineralocorticoid receptors (MR) has been implicated in vascular dysfunction of diabetes. Underlying mechanisms are elusive. Therefore, we investigated the role of Rho kinase (ROCK) in aldosterone/MR signaling and vascular dysfunction in a model of diabetes. Diabetic obese mice (db/db) and control counterparts (db/+) were treated with MR antagonist (MRA, potassium canrenoate, 30 mg/kg/day, 4 weeks) or ROCK inhibitor, fasudil (30 mg/kg/day, 3 weeks). Plasma aldosterone was increased in db/db versus db/+. This was associated with enhanced vascular MR signaling. Norepinephrine (NE)-induced contraction was increased in arteries from db/db mice. These responses were attenuated in mice treated with canrenoate or fasudil. Db/db mice displayed hypertrophic remodeling and increased arterial stiffness, improved by MR blockade. Vascular calcium sensitivity was similar between depolarized arteries from db/+ and db/db. Vascular hypercontractility in db/db mice was associated with increased myosin light chain phosphorylation and reduced expression of PKG-1 alpha. Vascular RhoA/ROCK signaling and expression of pro-inflammatory and pro-fibrotic markers were exaggerated in db/db mice, effects that were attenuated by MRA. Fasudil, but not MRA, improved vascular insulin sensitivity in db/db mice, evidenced by normalization of Irs1 phosphorylation. Our data identify novel pathways involving MR-RhoA/ROCK-PKG-1 that underlie vascular dysfunction and injury in diabetic mice.

  • 288.
    Cederberg, Jonas
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Oxidative stress, antioxidative defence and outcome of gestation in experimental diabetic pregnancy.2001Inngår i: Thesis, Acta Univ Upsal, Vol. 1008Annet (Annet vitenskapelig)
  • 289.
    Cederberg, Jonas
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Oxidative stress, antioxidative defence and outcome of gestation in experimental diabetic pregnancy2001Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Maternal type 1 diabetes is associated with an increased risk for foetal malformations. The mechanism by which diabetes is teratogenic is not fully known. Previous studies have demonstrated that radical oxygen species can contribute to the teratogenicity of glucose and diabetes. The aim of the present work was to study different aspects of free radical damage and antioxidant defence in experimental diabetic pregnancy.

    The activity of the antioxidant enzyme catalase and the mRNA levels of antioxidant enzymes in embryos of normal and diabetic rats of two strains were measured. The catalase activity was higher in embryos of a malformation-resistant strain than in a malformation-prone strain, the difference increased further when the mother was diabetic. Maternal diabetes increased embryonic mRNA levels of catalase and manganese superoxide dismutase in the malformation-resistant strain, but not in the malformation-prone strain. Embryos of the malformation-prone rat thus had lower antioxidative defence than embryos of the malformation-resistant strain.

    Administration of either vitamin E or vitamin C has previously been shown to protect embryos from maldevelopment in experimental diabetic pregnancy. The vitamins were used together in this thesis to yield protection in both the lipid and aqueous phase. The protective effect was not higher than what had been achieved using the vitamins individually. No synergistic effect was thus found using the two antioxidants together.

    The urinary excretion of the lipid peroxidation marker 8-iso-PGF was increased in pregnant dia-betic rats compared with non-diabetic controls, as was the plasma content of carbonylated proteins. Carbonylated proteins and TBARS concentrations were increased in foetal livers in diabetic pregnancy. However, no increased concentration of 8-iso-PGF was found in the amniotic fluid of pregnant diabetic rats. Both lipids and proteins were thus oxidatively modified in experimental diabetic pregnancy. It is concluded that experimental diabetic pregnancy is associated with increased oxidative stress and that the embryonic antioxidant defence is likely to be of importance for normal development in a diabetic environment.

  • 290.
    Cederberg, Jonas
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Basu, Samar
    Institutionen för folkhälso- och vårdvetenskap.
    Eriksson, Ulf J
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Increased rate of lipid peroxidation and protein carbonylation inexperimental diabetic pregnancy.2001Inngår i: Diabetologia, Vol. 44, s. 766-774Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Diabetic pregnancy displays increased incidence of congenital malformations and elevated levels of lipid peroxides in the offspring. The aim of the present work was to study if exogenous administration of one lipid peroxide, the isoprostane 8-iso-PGF(2alpha), is teratogenic per se in rat embryos in vitro, and if such teratological effects may be diminished by supplementation of an antioxidative agent, i.e., N-acetylcysteine or superoxide dismutase, to the culture medium. METHODS: Day-9 embryos were cultured in vitro for 48 hr and subjected to 8-iso-PGF(2alpha) with and without N-acetylcysteine or superoxide dismutase. RESULTS: Addition of 2 micromol/l of the isoprostane 8-iso-PGF(2alpha) to the culture medium caused high malformation rate, decreased protein and DNA contents, decreased somite number and crown-rump-length as well as marked accumulation of the isoprostane in the embryonic tissues. Adding N-acetylcysteine or superoxide dismutase to the culture medium with isoprostane normalized almost all morphological and biochemical parameters, including the elevated tissue concentration of 8-iso-PGF(2alpha). CONCLUSIONS: Results indicate that the isoprostane (8-iso-PGF(2alpha)) serves both as an oxidative stress indicator and a teratogenic agent. The findings support earlier studies of enhanced oxidative stress and increased malformation rate in embryos exposed to a diabetes-like environment, and suggest prevention of dysmorphogenesis by administration of antioxidative agents.

  • 291.
    Cederberg, Jonas
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Eriksson, Ulf J
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Antioxidative treatment of pregnant diabetic rats diminishes embryonic dysmorphogenesis.2005Inngår i: Birth Defects Res A Clin Mol Teratol, ISSN 1542-0752, Vol. 73, nr 7, s. 498-505Artikkel i tidsskrift (Fagfellevurdert)
  • 292.
    Cederberg, Jonas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Eriksson, Ulf J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Decreased catalase activity in malformation-prone embryos of diabetic rats1997Inngår i: Teratology, ISSN 0040-3709, E-ISSN 1096-9926, Vol. 56, nr 6, s. 350-357Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The risk for congenital malformation is increased in diabetic pregnancy. An excess of radical oxygen species (ROS) in the embryo has been suggested as a major teratogenic mechanism. We have used 2 rat strains, denoted H and U, with different catalase isoenzymes to study if the type of ROS scavenging enzyme may be of importance for the embryonic dysmorphogenesis in diabetic pregnancy. Rats were mated H x H and U x U, and about half of the females had streptozotocin-induced diabetes. Embryos were harvested from female rats on day 11 and day 20 of pregnancy. On day 11, the H embryos showed larger crown-rump length (3.9 mm) than the U embryos (2.9 mm), a difference that remained in the embryos of diabetic rats (3.1 mm and 2.5 mm in the H and U strains, respectively). H embryos displayed higher activity of catalase (1.8 +/- 0.1 U/micrograms DNA) than U embryos (1.1 +/- 0.1 U/micrograms DNA), and the difference increased further when the H and U mothers were diabetic (H: 2.1 +/- 0.2 U/micrograms DNA, U: 0.6 +/- 0.1 U/micrograms DNA). In the day-20 fetuses, diabetes in the mother caused increased resorption rate in both strains (from 3.2% to 10.6% in H rats, from 6.8% to 39.5% in U rats), and high rate of congenital malformations in the U strain (H: 0% malformations, U: 20% malformations). We found a strain-related difference in embryo catalase activity with higher activity in the teratogenically resistant H embryos compared to the malformation-prone U embryos. Provided that this difference between the strains signifies a genetic difference of functional antioxidative importance, the results may suggest that catalase enzyme activity has a protective role in opposing embryonic dysmorphogenesis in diabetic rat pregnancy

  • 293.
    Cederberg, Jonas
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Galli, Joakim
    Luthman, Holger
    Eriksson, Ulf J
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Increased mRNA levels of Mn-SOD and catalase in embryos of diabetic rats from a malformation-resistant strain.2000Inngår i: Diabetes, Vol. 49, s. 101-107Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Previous studies have suggested that reactive oxygen species (ROS) are mediators in the teratogenic process of diabetic pregnancy. In an animal model for diabetic pregnancy, offspring of the H rat strain show minor dysmorphogenesis when the mother is diabetic, whereas the offspring of diabetic rats of a sister strain, U, display major morphologic malformations. Earlier studies have shown that embryonic catalase activity is higher in the H than in the U strain, and maternal diabetes increases this difference in activity. The aim of this study was to characterize the influence of genetic predisposition on diabetic embryopathy by comparing the mRNA levels of ROS-metabolizing enzymes in the two strains. We determined the mRNA levels of catalase, glutathione peroxidase, gamma-glutamylcystein-synthetase, glutathione reductase, and superoxide dismutase (CuZn-SOD and Mn-SOD) in day 11 embryos of normal and diabetic H and U rats using semiquantitative reverse transcription-polymerase chain reaction. The mRNA levels of catalase and Mn-SOD were increased in H embryos as a response to maternal diabetes, and no differences were found for the other genes. Sequence analysis of the catalase promoter indicated that the difference in mRNA levels may result from different regulation of transcription. Sequence analysis of the catalase cDNA revealed no differences between the two strains in the translated region, suggesting that the previously observed difference in the electrophoretic mobility in zymograms is due to posttranslational modifications. An impaired expression of scavenging enzymes in response to ROS excess can thus be an integral part of a genetic predisposition to embryonic dysmorphogenesis.

  • 294.
    Cederberg, Jonas
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Picard, Jacques J.
    Eriksson, Ulf J
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Maternal diabetes in the rat impairs the formation of neural-crest derived cranial nerve ganglia in the offspring2003Inngår i: Diabetologia, Vol. 46, nr 9, s. 1245-1251Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIMS/HYPOTHESIS: Maternal diabetes mellitus increases the risk for fetal malformations. Several of these malformations are found in organs and tissues derived from the neural crest. Previous studies have shown changes in fetal organs of neural crest origin in experimental diabetes and changes in migration of neural crest cells exposed to high glucose in vitro. METHODS: We used whole-mount neurofilament staining of embryos from normal and diabetic mothers to investigate the development of cranial nerve ganglia. Neural tube explants were cultured in 10 and 40 mmol/l glucose and cell death and caspase activity was measured with flow cytometry. RESULTS: The development of cranial ganglia V, VII, VIII, IX and X was impaired in day 10-11 embryos of diabetic rats. There was also a higher rate of cell death of neural crest derived cells cultured in 40 mmol/l glucose for 20 h (35% compared to 12% in 10 mmol/l). However, exposure of cells to 40 mmol/l glucose in culture did not increase the activation of the cell death effector proteins-caspases-measured as cellular binding of the activated caspase marker VAD-FMK. This suggests that the cell death is not caused by caspase-dependent apoptosis or that the caspases are activated at an earlier stage. CONCLUSION/INTERPRETATION: The development of neural crest-derived structures is disturbed already at the organogenic period in embryos of diabetic rats and this deteriorated development could be due to high-glucose induced increase in cell death of neural crest derived cells.

  • 295.
    Cederberg, Jonas
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Siman, C Martin
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Eriksson, Ulf J
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Combined treatment with vitamin E and vitamin C decreases oxidative stressand improves fetal outcome in experimental diabetic pregnancy.2001Inngår i: Pediatr Res, Vol. 49, s. 755-762Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The aim was to investigate whether dietary supplementation of a combination of the two antioxidants, vitamin E and vitamin C, would protect the fetus in diabetic rat pregnancy at a lower dose than previously used. Normal and streptozotocin-induced diabetic rats were mated and given standard food or food supplemented with either 0.5% vitamin E + 1% vitamin C or 2% vitamin E + 4% vitamin C. At gestational d 20, gross morphology and weights of fetuses were evaluated. Vitamins E and C and thiobarbituric acid reactive substances were measured in maternal and fetal compartments. In addition, protein carbonylation was estimated in fetal liver. Maternal diabetes increased the rate of malformation and resorption in the offspring. High-dose antioxidant supplementation decreased fetal dysmorphogenesis to near normal levels. The low-dose group showed malformations and resorptions at an intermediate rate between the untreated and the high-dose groups. Thiobarbituric acid reactive substances were increased in fetal livers of diabetic rats and reduced to normal levels already by low-dose antioxidative treatment. Protein carbonylation rate was also increased in fetal liver of diabetic rats; it was normalized by high-dose treatment but only partially reduced by low-dose antioxidants. We conclude that combined antioxidative treatment with vitamins E and C decreases fetal malformation rate and diminishes oxygen radical-related tissue damage. However, no synergistic effect between the two antioxidants was noted, a result that may influence future attempts to design antiteratogenic treatments in diabetic pregnancy. Oxidatively modified proteins may be teratogenically important mediators in diabetic embryopathy.

  • 296.
    Cen, Jing
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Free fatty acids and insulin hypersecretion studied in human islets2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Free fatty acid (FFA) levels are increased in many obese subjects. High FFA levels stimulate the pancreatic beta-cells but have negative long-term effects. In obese children with high FFA levels circulating insulin concentration is high early in life but decline with age precipitating the development of type 2 diabetes mellitus (T2DM). The present study aims at preventing this development of T2DM by defining underlying mechanisms of insulin hypersecretion. Such mechanisms will be identified by studying regulation of insulin secretion from human pancreatic islets and human EndoC-βH1 cells exposed to elevated FFA levels.

    We found that elevated concentrations of FFAs acutely stimulate insulin from human pancreatic islets at fasting blood glucose level, with mono-unsatured being more potent than saturated fatty acids. Enhanced secretion was associated with increased glycolytic flux and mitochondrial respiration. Continued exposure to elevated palmitate levels for up to 2 days accentuated insulin secretion, whereas 7 days’ exposure caused secretory decline. Metformin prevented insulin hypersecretion from human islets treated with palmitate for 2 days by decreasing mitochondrial metabolism. In islets exposed to palmitate for 7 days metformin improved insulin secretion by enhancing calcium binding protein sorcin levels and thereby reducing ER stress and apoptosis. Downregulation of sorcin had negative effects on insulin secretion, mitochondrial metabolism and ER stress in human islets and EndoC-βH1 cells. Specific cellular pathways involved in insulin hypersecretion and secretory decline were identified by microarray expression analysis and subsequent bioinformatics in human islets cultured with palmitate for 0, 4, 12 hours, 1, 2, and 7 days.

    In conclusion, beta-cells respond to elevated levels of FFAs by initially augmenting insulin release followed by declining secretory levels after prolonged exposure. Metformin normalizes these secretory aberrations. Specific signaling pathways and proteins including sorcin contribute to the secretory alterations induced by palmitate. When developing strategies for prevention of T2DM in obese children with elevated FFA levels, metformin should be considered as well as novel strategies involving sorcin and the identified specific pathways.

     

    Delarbeid
    1. Fatty acids stimulate insulin secretion from human pancreatic islets at fasting glucose concentrations via mitochondria-dependent and -independent mechanisms
    Åpne denne publikasjonen i ny fane eller vindu >>Fatty acids stimulate insulin secretion from human pancreatic islets at fasting glucose concentrations via mitochondria-dependent and -independent mechanisms
    2016 (engelsk)Inngår i: Nutrition & Metabolism, ISSN 1743-7075, E-ISSN 1743-7075, Vol. 13, artikkel-id 59Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background: Free fatty acids (FFAs) acutely stimulate insulin secretion from pancreatic islets. Conflicting results have been presented regarding this effect at non-stimulatory glucose concentration, however. The aim of our study was to investigate how long-chain FFAs affect insulin secretion from isolated human pancreatic islets in the presence of physiologically fasting glucose concentrations and to explore the contribution of mitochondria to the effects on secretion. Methods: Insulin secretion from human pancreatic islets was measured from short-term static incubation or perfusion system at fasting glucose concentration (5.5 mM) with or without 4 different FFAs (palmitate, palmitoleate, stearate, and oleate). The contribution of mitochondrial metabolism to the effects of fatty acid-stimulated insulin secretion was explored. Results: The average increase in insulin secretion, measured from statically incubated and dynamically perifused human islets, was about 2-fold for saturated free fatty acids (SFAs) (palmitate and stearate) and 3-fold for mono-unsaturated free fatty acids (MUFAs) (palmitoleate and oleate) compared with 5.5 mmol/l glucose alone. Accordingly, MUFAs induced 50 % and SFAs 20 % higher levels of oxygen consumption compared with islets exposed to 5.5 mmol/l glucose alone. The effect was due to increased glycolysis. When glucose was omitted from the medium, addition of the FFAs did not affect oxygen consumption. However, the FFAs still stimulated insulin secretion from the islets although secretion was more than halved. The mitochondria-independent action was via fatty acid metabolism and FFAR1/GPR40 signaling. Conclusions: The findings suggest that long-chain FFAs acutely induce insulin secretion from human islets at physiologically fasting glucose concentrations, with MUFAs being more potent than SFAs, and that this effect is associated with increased glycolytic flux and mitochondrial respiration.

    Emneord
    Insulin secretion, Human pancreatic islets, Saturated fatty acids, Monounsaturated fatty acids, Mitochondrial respiration
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-305932 (URN)10.1186/s12986-016-0119-5 (DOI)000384583400001 ()27582778 (PubMedID)
    Tilgjengelig fra: 2016-11-14 Laget: 2016-10-24 Sist oppdatert: 2018-06-27bibliografisk kontrollert
    2. Mechanisms of beneficial effects of metformin on fatty acid-treated human islets
    Åpne denne publikasjonen i ny fane eller vindu >>Mechanisms of beneficial effects of metformin on fatty acid-treated human islets
    2018 (engelsk)Inngår i: Journal of Molecular Endocrinology, ISSN 0952-5041, E-ISSN 1479-6813, Vol. 61, nr 3, s. 91-99Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Elevated levels of palmitate accentuate glucose-stimulated insulin secretion (GSIS) after short-term and cause beta-cell dysfunction after prolonged exposure. We investigated whether metformin, the first-line oral drug for treatment of T2DM, has beneficial effects on FFA-treated human islets and the potential mechanisms behind the effects. Insulin secretion, oxygen consumption rate (OCR), AMPK activation, endoplasmic reticulum (ER) stress and apoptosis were examined in isolated human islets after exposure to elevated levels of palmitate in the absence or presence of metformin. Palmitate exposure doubled GSIS after 2 days but halved after 7 days compared with control. Inclusion of metformin during palmitate exposure normalized insulin secretion both after 2 and 7 days. After 2-day exposure to palmitate, OCR and the marker of the adaptive arm of ER stress response (sorcin) were significantly raised, whereas AMPK phosphorylation, markers of pro-apoptotic arm of ER stress response (p-EIF2α and CHOP) and apoptosis (cleaved caspase 3) were not affected. Presence of metformin during 2-day palmitate exposure normalized OCR and sorcin levels. After 7-day exposure to palmitate, OCR and sorcin were not significantly different from control level, p-AMPK was reduced and p-EIF2α, CHOP and cleaved caspase 3 were strongly upregulated. Presence of metformin during 7-day culture with palmitate normalized the level of p-AMPK, p-EIF2α, CHOP and cleaved caspase 3 but significantly increased the level of sorcin. Our study demonstrates that metformin prevents early insulin hypersecretion and later decrease in insulin secretion from palmitate-treated human islets by utilizing different mechanisms.

    Emneord
    Metformin, palmitate, human islets, insulin secretion, mitochondrial respiration, ER stress
    HSV kategori
    Forskningsprogram
    Medicinsk cellbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-353691 (URN)10.1530/JME-17-0304 (DOI)000452706400005 ()30307162 (PubMedID)
    Forskningsfinansiär
    Swedish Diabetes Association, DIA 2016-146EU, FP7, Seventh Framework Programme, 279 153Ernfors Foundation, 170504
    Tilgjengelig fra: 2018-06-27 Laget: 2018-06-27 Sist oppdatert: 2019-01-11bibliografisk kontrollert
    3. Sorcin counteracts lipotoxicity in palmitate-exposed human beta-cells
    Åpne denne publikasjonen i ny fane eller vindu >>Sorcin counteracts lipotoxicity in palmitate-exposed human beta-cells
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    In obese subjects elevated circulating levels of free fatty acids (FFAs) have been connected with hyperinsulinemia and development of type 2 diabetes. In human islets insulin secretion is accentuated when palmitate concentration is increased for short time periods. Our previous findings indicated that increased sorcin expression may delay development of ER stress in such human islets exposed to palmitate. In the present study we tested this hypothesis by using human islets and human EndoC-βH1 cells transfected with lenti-viral transduction particles of anti-sorcin. Human islets and EndoC-βH1 cells treated with palmitate for 2 days induced sorcin expression. The beta-cells showed enhanced glucose-stimulated insulin secretion (GSIS), mitochondrial respiration and glycolysis and no alterations in ER stress and apoptosis. When sorcin was knocked down, palmitate-induced upregulation of sorcin was reduced. The beta-cells showed reduced GSIS, mitochondrial respiration and glycolysis and increased ER stress and apoptosis. We conclude that enhanced sorcin levels play a role in preventing lipotoxicity in beta-cells exposed to elevated palmitate levels for prolonged time periods.

    Emneord
    Sorcin, palmitate, human islets, EndoC-βH1 cells, insulin secretion, mitochondrial respiration, ER stress
    HSV kategori
    Forskningsprogram
    Medicinsk cellbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-355088 (URN)
    Tilgjengelig fra: 2018-06-27 Laget: 2018-06-27 Sist oppdatert: 2018-06-27
    4. Identification of early biological changes in palmitate-treated isolated human islets.
    Åpne denne publikasjonen i ny fane eller vindu >>Identification of early biological changes in palmitate-treated isolated human islets.
    Vise andre…
    2018 (engelsk)Inngår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 19, artikkel-id 629Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background: Long-term exposure to elevated levels of free fatty acids (FFAs) is deleterious for beta-cell function and may contribute to development of type 2 diabetes mellitus (T2DM). Whereas mechanisms of impaired glucose-stimulated insulin secretion (GSIS) in FFA-treated beta-cells have been intensively studied, biological events preceding the secretory failure, when GSIS is accentuated, are poorly investigated. To identify these early events, we performed genome-wide analysis of gene expression in isolated human islets exposed to fatty acid palmitate for different time periods.

    Results: Palmitate-treated human islets showed decline in beta-cell function starting from day two. Affymetrix Human Transcriptome Array 2.0 identified 903 differentially expressed genes (DEGs). Mapping of the genes onto pathways using KEGG pathway enrichment analysis predicted four islet biology-related pathways enriched prior but not after the decline of islet function and three pathways enriched both prior and after the decline of islet function. DEGs from these pathways were analyzed at the transcript level. The results propose that in palmitate-treated human islets, at early time points, protective events, including up-regulation of metallothioneins, tRNA synthetases and fatty acid-metabolising proteins, dominate over deleterious events, including inhibition of fatty acid detoxification enzymes, which contributes to the enhanced GSIS. After prolonged exposure of islets to palmitate, the protective events are outweighed by the deleterious events, which leads to impaired GSIS.

    Conclusions: The study identifies temporal order between different cellular events, which either promote or protect from beta-cell failure. The sequence of these events should be considered when developing strategies for prevention and treatment of the disease.

    sted, utgiver, år, opplag, sider
    BioMed Central, UK: , 2018
    Emneord
    palmitate, human islets, insulin secretion, Human Transcriptome Array
    HSV kategori
    Forskningsprogram
    Medicinsk cellbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-355082 (URN)10.1186/s12864-018-5008-z (DOI)000442532000008 ()30134843 (PubMedID)
    Forskningsfinansiär
    EU, FP7, Seventh Framework Programme, 279 153
    Tilgjengelig fra: 2018-06-27 Laget: 2018-06-27 Sist oppdatert: 2018-10-05bibliografisk kontrollert
  • 297.
    Cen, Jing
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Sargsyan, Ernest
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Bergsten, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Fatty acids stimulate insulin secretion from human pancreatic islets at fasting glucose concentrations via mitochondria-dependent and -independent mechanisms2016Inngår i: Nutrition & Metabolism, ISSN 1743-7075, E-ISSN 1743-7075, Vol. 13, artikkel-id 59Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Free fatty acids (FFAs) acutely stimulate insulin secretion from pancreatic islets. Conflicting results have been presented regarding this effect at non-stimulatory glucose concentration, however. The aim of our study was to investigate how long-chain FFAs affect insulin secretion from isolated human pancreatic islets in the presence of physiologically fasting glucose concentrations and to explore the contribution of mitochondria to the effects on secretion. Methods: Insulin secretion from human pancreatic islets was measured from short-term static incubation or perfusion system at fasting glucose concentration (5.5 mM) with or without 4 different FFAs (palmitate, palmitoleate, stearate, and oleate). The contribution of mitochondrial metabolism to the effects of fatty acid-stimulated insulin secretion was explored. Results: The average increase in insulin secretion, measured from statically incubated and dynamically perifused human islets, was about 2-fold for saturated free fatty acids (SFAs) (palmitate and stearate) and 3-fold for mono-unsaturated free fatty acids (MUFAs) (palmitoleate and oleate) compared with 5.5 mmol/l glucose alone. Accordingly, MUFAs induced 50 % and SFAs 20 % higher levels of oxygen consumption compared with islets exposed to 5.5 mmol/l glucose alone. The effect was due to increased glycolysis. When glucose was omitted from the medium, addition of the FFAs did not affect oxygen consumption. However, the FFAs still stimulated insulin secretion from the islets although secretion was more than halved. The mitochondria-independent action was via fatty acid metabolism and FFAR1/GPR40 signaling. Conclusions: The findings suggest that long-chain FFAs acutely induce insulin secretion from human islets at physiologically fasting glucose concentrations, with MUFAs being more potent than SFAs, and that this effect is associated with increased glycolytic flux and mitochondrial respiration.

  • 298.
    Cen, Jing
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Sargsyan, Ernest
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Bergsten, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Metformin restores insulin secretion from palmitate-treated human islets by normalising mitochondrial metabolism and reducing ER stress and apoptosis2017Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, s. S47-S47Artikkel i tidsskrift (Annet vitenskapelig)
  • 299.
    Cen, Jing
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Sargsyan, Ernest
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Bergsten, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Sorcin counteracts lipotoxicity in palmitate-exposed human beta-cellsManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    In obese subjects elevated circulating levels of free fatty acids (FFAs) have been connected with hyperinsulinemia and development of type 2 diabetes. In human islets insulin secretion is accentuated when palmitate concentration is increased for short time periods. Our previous findings indicated that increased sorcin expression may delay development of ER stress in such human islets exposed to palmitate. In the present study we tested this hypothesis by using human islets and human EndoC-βH1 cells transfected with lenti-viral transduction particles of anti-sorcin. Human islets and EndoC-βH1 cells treated with palmitate for 2 days induced sorcin expression. The beta-cells showed enhanced glucose-stimulated insulin secretion (GSIS), mitochondrial respiration and glycolysis and no alterations in ER stress and apoptosis. When sorcin was knocked down, palmitate-induced upregulation of sorcin was reduced. The beta-cells showed reduced GSIS, mitochondrial respiration and glycolysis and increased ER stress and apoptosis. We conclude that enhanced sorcin levels play a role in preventing lipotoxicity in beta-cells exposed to elevated palmitate levels for prolonged time periods.

  • 300.
    Cen, Jing
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Sargsyan, Ernest
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Molecular Neuroscience Group, Institute of Molecular Biology, National Academy of Sciences, Yerevan, Armenia.
    Forslund, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Pediatrisk inflammationsforskning.
    Bergsten, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Pediatrisk inflammationsforskning.
    Mechanisms of beneficial effects of metformin on fatty acid-treated human islets2018Inngår i: Journal of Molecular Endocrinology, ISSN 0952-5041, E-ISSN 1479-6813, Vol. 61, nr 3, s. 91-99Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Elevated levels of palmitate accentuate glucose-stimulated insulin secretion (GSIS) after short-term and cause beta-cell dysfunction after prolonged exposure. We investigated whether metformin, the first-line oral drug for treatment of T2DM, has beneficial effects on FFA-treated human islets and the potential mechanisms behind the effects. Insulin secretion, oxygen consumption rate (OCR), AMPK activation, endoplasmic reticulum (ER) stress and apoptosis were examined in isolated human islets after exposure to elevated levels of palmitate in the absence or presence of metformin. Palmitate exposure doubled GSIS after 2 days but halved after 7 days compared with control. Inclusion of metformin during palmitate exposure normalized insulin secretion both after 2 and 7 days. After 2-day exposure to palmitate, OCR and the marker of the adaptive arm of ER stress response (sorcin) were significantly raised, whereas AMPK phosphorylation, markers of pro-apoptotic arm of ER stress response (p-EIF2α and CHOP) and apoptosis (cleaved caspase 3) were not affected. Presence of metformin during 2-day palmitate exposure normalized OCR and sorcin levels. After 7-day exposure to palmitate, OCR and sorcin were not significantly different from control level, p-AMPK was reduced and p-EIF2α, CHOP and cleaved caspase 3 were strongly upregulated. Presence of metformin during 7-day culture with palmitate normalized the level of p-AMPK, p-EIF2α, CHOP and cleaved caspase 3 but significantly increased the level of sorcin. Our study demonstrates that metformin prevents early insulin hypersecretion and later decrease in insulin secretion from palmitate-treated human islets by utilizing different mechanisms.

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