Thioredoxin-Interacting Protein Deficiency Protects against Diabetic Nephropathy

• Published in: Journal of the American Society of Nephrology 2015-12, Vol.26 (12), p.2963-2977
• Main Authors: Shah, Anu, Xia, Ling, Masson, Elodie A Y, Gui, Chloe, Momen, Abdul, Shikatani, Eric A, Husain, Mansoor, Quaggin, Susan, John, Rohan, Fantus, I G
• Format: Article
• Language: English
• Subjects: Albuminuria - etiology; Animals; Antigens, Differentiation - analysis; Apoptosis - drug effects; Apoptosis - genetics; Basic Research; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cells, Cultured; Collagen Type IV - analysis; Creatinine - blood; Cystatin C - blood; Diabetes Mellitus, Experimental - chemically induced; Diabetes Mellitus, Experimental - metabolism; Diabetic Nephropathies - metabolism; Fibrosis; Glomerular Basement Membrane - pathology; Glucose - pharmacology; Interleukin-1beta - genetics; Kidney Glomerulus - chemistry; Kidney Glomerulus - pathology; Life Sciences; Membrane Proteins - analysis; Mice; Mice, Knockout; Mitochondria - drug effects; Mitochondria - genetics; Mitochondria - metabolism; NADPH Oxidase 4; NADPH Oxidases - genetics; NADPH Oxidases - metabolism; Oxidative Stress; Oxygen - metabolism; Podocytes - chemistry; Podocytes - drug effects; Podocytes - pathology; Repressor Proteins - analysis; RNA, Messenger - analysis; Streptozocin; Thioredoxins - genetics; Thioredoxins - metabolism; Transforming Growth Factor beta1 - analysis
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/asn.2014050528

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.