Thioredoxin-interacting protein deficiency protects against diabetic nephropathy

Anu Shah, Ling Xia, Elodie A.Y. Masson, Chloe Gui, Abdul Momen, Eric A. Shikatani, Mansoor Husain, Susan Quaggin, Rohan John, I. G. Fantus*

*Corresponding author for this work

Research output: Contribution to journalArticle

37 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2963-2977
Number of pages15
JournalJournal of the American Society of Nephrology
Volume26
Issue number12
DOIs
StatePublished - Dec 2015

ASJC Scopus subject areas

  • Nephrology

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    Shah, A., Xia, L., Masson, E. A. Y., Gui, C., Momen, A., Shikatani, E. A., Husain, M., Quaggin, S., John, R., & 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