Thioredoxin-interacting protein deficiency protects against diabetic nephropathy

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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, mitogenactivated protein kinase phosphorylation, and collagen expression.Here,we investigated the potential roleof 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 inWTdiabeticmice. Additionally, onlyWTdiabeticmice showed significant increases in oxidative stress (nitrotyrosine, urinary 8-hydroxy-2-deoxy-guanosine) and inflammation (IL-1bmRNA, F4/80 immunohistochemistry). Expression levels ofNox4-encodedmRNA 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 2 generation and apoptosis. These data indicate that TxNIP has a critical role in the progression ofDNandmay be a promising therapeutic target.

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Shah, A., Xia, L., Masson, E. A. Y., Gui, C., Momen, A., Shikatani, E. A., … Fantus, I. G. (2015). Thioredoxin-interacting protein deficiency protects against diabetic nephropathy. Journal of the American Society of Nephrology, 26(12), 2963–2977. https://doi.org/10.1681/ASN.2014050528

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