Oxidative stress induces claudin-2 nitration in experimental type 1 diabetic nephropathy |
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| Affiliation: | 1. Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, United States;2. Clement J. Zablocki VA Medical Center, Milwaukee, WI, United States;1. Institute of Epidemiology and Medical Biometry, ZIBMT, Ulm University, 89081 Ulm, Germany;2. German Centre for Diabetes Research (DZD), 85764 Munich, Neuherberg, Germany;3. Department of Internal Medicine I, Division of Endocrinology, University Hospital, 60590 Frankfurt am Main, Germany;4. Geriatric Centre Ulm/Alb-Donau, Geriatric Medicine at Ulm University, Agaplesion Bethesda Hospital Ulm, 89081 Ulm, Germany;5. Clinic for Gastroenterology and Gastrointestinal Oncology, Endocrine Unit, University Medical Centre Göttingen,37075 Göttingen, Germany;6. Hospital zum Heiligen Geist Kempen, Akademisches Lehrkrankenhaus, Heinrich Heine University Düsseldorf, 47906 Kempen, Germany;7. Department of Internal Medicine, Hospital Melk, 3390 Melk, Austria;8. Department of General Internal Medicine, Endocrinology and Diabetology, Helios Kliniken Schwerin, 19049 Schwerin, Germany;1. ZIEL Research Center of Nutrition and Food Sciences, Department of Biochemistry, Technical Universtiy of Munich, Gregor-Mendel-Str. 2, Freising 85350, Germany;2. Pharmaceutical Institute, Department of Pharmaceutical Biology, Christian-Albrechts-University of Kiel, Gutenbergstrasse 76, Kiel 24118, Germany;3. BioActive Food GmbH (HV), Am Ihlsee 36a, Bad Segeberg 23795, Germany |
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| Abstract: | Renal complications in diabetes are severe and may lead to renal insufficiency. Early alterations in tight junction (TJ) proteins in diabetic nephropathy (DN) have not been explored and the role of oxidative stress in their disassembly has been poorly characterized. We investigated the expression and distribution of TJ proteins: claudin-5 in glomeruli (GL), occludin and claudin-2 in proximal tubules (PTs), and ZO-1 and claudin-1, -4, and -8 in distal tubules (DTs) of rats 21 days after streptozotocin injection. Redox status along the nephron segments was evaluated. Diabetes increased kidney injury molecule-1 expression. Expression of sodium glucose cotransporters (SGLT1 and SGLT2) and facilitative glucose transporter (GLUT2) was induced. Increased oxidative stress was present in GL and PTs and to a lesser extent in DTs (measured by superoxide production and PKCβ2 expression), owing to NADPH oxidase activation and uncoupling of the endothelial nitric oxide synthase-dependent pathway. Claudin-5, occludin, and claudin-2 expression was decreased, whereas claudin-4 and -8 expression increased. ZO-1 was redistributed from membrane to cytosol. Increased nitration of tyrosine residues in claudin-2 was found, which might contribute to decrement of this protein in proximal tubule. In contrast, occludin was not nitrated. We suggest that loss of claudin-2 is associated with increased natriuresis and that loss of glomerular claudin-5 might explain early presence of proteinuria. These findings suggest that oxidative stress is related to alterations in TJ proteins in the kidney that are relevant to the pathogenesis and progression of DN and for altered sodium regulation in diabetes. |
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| Keywords: | Renal tight junctions Oxidative stress Claudins Protein tyrosine nitration Glucose transporters Free radicals |
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