title: Thioredoxin-Interacting Protein Deficiency Protects against Diabetic Nephropathy.
abstract: Expression of thioredoxin-interacting protein (TxNIP), an endogenous inhibitor of the thiol oxidoreductase thioredoxin, is augmented by high glucose (HG) and promotes oxidative stress. We previously reported that TxNIP-deficient mesangial cells showed protection from HG-induced reactive oxygen species, mitogen-activated protein kinase phosphorylation, and collagen expression. Here, we investigated the potential role of TxNIP in the pathogenesis of diabetic nephropathy (DN) in vivo. Wild-type (WT) control, TxNIP(-/-), and TxNIP(+/-) mice were rendered equally diabetic with low-dose streptozotocin. In contrast to effects in WT mice, diabetes did not increase albuminuria, proteinuria, serum cystatin C, or serum creatinine levels in TxNIP(-/-) mice. Whereas morphometric studies of kidneys revealed a thickened glomerular basement membrane and effaced podocytes in the diabetic WT mice, these changes were absent in the diabetic TxNIP(-/-) mice. Immunohistochemical analysis revealed significant increases in the levels of glomerular TGF-β1, collagen IV, and fibrosis only in WT diabetic mice. Additionally, only WT diabetic mice showed significant increases in oxidative stress (nitrotyrosine, urinary 8-hydroxy-2-deoxy-guanosine) and inflammation (IL-1β mRNA, F4/80 immunohistochemistry). Expression levels of Nox4-encoded mRNA and protein increased only in the diabetic WT animals. A significant loss of podocytes, assessed by Wilms' tumor 1 and nephrin staining and urinary nephrin concentration, was found in diabetic WT but not TxNIP(-/-) mice. Furthermore, in cultured human podocytes exposed to HG, TxNIP knockdown with siRNA abolished the increased mitochondrial O2 (-) generation and apoptosis. These data indicate that TxNIP has a critical role in the progression of DN and may be a promising therapeutic target.
authors: Department of Medicine and Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto General Research Institute, University Health Network, Department of Physiology, Banting and Best Diabetes Centre, and.
authors: Anu
authors: A
authors: Shah
authors: Department of Medicine and Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto General Research Institute, University Health Network, Banting and Best Diabetes Centre, and.
authors: Ling
authors: L
authors: Xia
authors: Department of Medicine and Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Banting and Best Diabetes Centre, and.
authors: Elodie A Y
authors: EA
authors: Masson
authors: Department of Medicine and Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Banting and Best Diabetes Centre, and.
authors: Chloe
authors: C
authors: Gui
authors: Toronto General Research Institute, University Health Network.
authors: Abdul
authors: A
authors: Momen
authors: Toronto General Research Institute, University Health Network, Department of Pathology and Laboratory Medicine, University of Toronto, Toronto, Ontario, Canada, and.
authors: Eric A
authors: EA
authors: Shikatani
authors: Toronto General Research Institute, University Health Network.
authors: Mansoor
authors: M
authors: Husain
authors: Department of Medicine and Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Banting and Best Diabetes Centre, and Feinberg Cardiovascular Research Institute, Division of Medicine-Nephrology, Northwestern Feinberg School of Medicine, Chicago, Illinois.
authors: Susan
authors: S
authors: Quaggin
authors: Toronto General Research Institute, University Health Network, Department of Pathology and Laboratory Medicine, University of Toronto, Toronto, Ontario, Canada, and.
authors: Rohan
authors: R
authors: John
authors: Department of Medicine and Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto General Research Institute, University Health Network, Department of Physiology, Banting and Best Diabetes Centre, and gfantus@mtsinai.on.ca.
authors: I G
authors: IG
authors: Fantus
mesh_terms: D000419:Albuminuria / Q000209:etiology; D000818:Animals; D000943:Antigens, Differentiation / Q000032:analysis; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000032:analysis; D003404:Creatinine / Q000097:blood; D055316:Cystatin C / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism*; D005355:Fibrosis; D050533:Glomerular Basement Membrane / Q000473:pathology; D005947:Glucose / Q000494:pharmacology; D053583:Interleukin-1beta / Q000235:genetics; D007678:Kidney Glomerulus / Q000737:chemistry / Q000473:pathology; D008565:Membrane Proteins / Q000032:analysis; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D050199:Podocytes / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D012097:Repressor Proteins / Q000032:analysis; D013311:Streptozocin; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000032:analysis; D025721:WT1 Proteins
chemical_list: D000943:Antigens, Differentiation; D002352:Carrier Proteins; D024141:Collagen Type IV; D055316:Cystatin C; D053583:Interleukin-1beta; D008565:Membrane Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D053773:Transforming Growth Factor beta1; C445672:Txnip protein, mouse; D025721:WT1 Proteins; C000602896:WT1 protein, mouse; C036763:monocyte-macrophage differentiation antigen; C113267:nephrin; D013879:Thioredoxins; D013311:Streptozocin; D003404:Creatinine; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; D005947:Glucose; D010100:Oxygen
keywords: diabetes mellitus; diabetic nephropathy; oxidative stress