Keap1 hypomorphism protects against ischemic and obstructive kidney disease

作     者：Tan, Roderick J. Chartoumpekis, Dionysios V. Rush, Brittney M. Zhou, Dong Fu, Haiyan Kensler, Thomas W. Liu, Youhua 

作者机构：Univ Pittsburgh Sch Med Dept Med Pittsburgh PA 15213 USA Univ Pittsburgh Sch Med Dept Pharmacol & Chem Biol Pittsburgh PA USA Univ Pittsburgh Sch Med Dept Pathol Pittsburgh PA USA 

出 版 物：《SCIENTIFIC REPORTS》 (科学报告)

年 卷 期：2016年第6卷第1期

页      面：36185-36185页

核心收录：

学科分类：12[管理学] 1201[管理学-管理科学与工程(可授管理学、工学学位)] 08[工学] 

基　　金：AHA Fellow-to-Faculty Award NIH [DK064005, DK091239, CA197220, T32 DK061296, P30 DK079307] 

摘      要：The Keap1/Nrf2 pathway is a master regulator of antioxidant, anti-inflammatory, and other cytoprotective mechanisms important in protection from kidney disease. For the first time in kidney disease, we describe the use of Keap1 hypomorphic mice, which possess Nrf2 hyperactivation. We exposed these mice and wild type controls to ischemia/reperfusion injury (IRI). The initial tubular injury at 24 hours post-IRI appeared to be unaffected, with the only observed difference being a decrease in inflammatory cytokine expression in the hypomorphs. However, we noted significant improvement in serum creatinine in the hypomorphs at 3 and 10 days after injury, and renal fibrosis was dramatically attenuated at the late timepoint. Assessment of Nrf2-regulated targets (GSTM1, GSTP1, NQO1) revealed higher expression in the hypomorphs at baseline. While injury tended to suppress these genes in wild-type mice, the suppression was attenuated or reversed in Keap1 hypomorphs, suggesting that protection in these mice was mediated by increased Nrf2 transcriptional activity. To assess the generalizability of our findings, we subjected the hypomorphs to unilateral ureteral obstruction (UUO) and again found significant protection and increased expression of Nrf2 targets. Overall, these results support the conclusion that the Nrf2 pathway is protective in a variety of kidney diseases.