title: Oxidative stress induces claudin-2 nitration in experimental type 1 diabetic nephropathy.
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.
authors.affiliation: Department of Physiology, Biophysics, and Neuroscience, Center for Research and Advanced Studies of the National Polytechnic Institute, México, DF 07360, Mexico.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Molina-Jijón
authors.affiliation: Department of Physiology, Biophysics, and Neuroscience, Center for Research and Advanced Studies of the National Polytechnic Institute, México, DF 07360, Mexico.
authors.forename: Rafael
authors.initials: R
authors.lastname: Rodríguez-Muñoz
authors.affiliation: Department of Physiology, Biophysics, and Neuroscience, Center for Research and Advanced Studies of the National Polytechnic Institute, México, DF 07360, Mexico.
authors.forename: María del Carmen
authors.initials: Mdel C
authors.lastname: Namorado
authors.affiliation: Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico, 04510 University City, DF, Mexico.
authors.forename: José
authors.initials: J
authors.lastname: Pedraza-Chaverri
authors.affiliation: Department of Physiology, Biophysics, and Neuroscience, Center for Research and Advanced Studies of the National Polytechnic Institute, México, DF 07360, Mexico. Electronic address: jreyes@fisio.cinvestav.mx.
authors.forename: José L
authors.initials: JL
authors.lastname: Reyes
mesh_terms: D000818:Animals; D015153:Blotting, Western; D057167:Claudins / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D047468:Immunoprecipitation; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D062725:Tight Junction Proteins / Q000378:metabolism
chemical_list: D057167:Claudins; C491874:Cldn2 protein, rat; D062725:Tight Junction Proteins
keywords: Claudins; Free radicals; Glucose transporters; Oxidative stress; Protein tyrosine nitration; Renal tight junctions