Sirt1 activation protects the mouse renal medulla from oxidative injury

作者：Wenjuan He, Yingying Wang, Ming‐Zhi Zhang, You Li, Linda Davis, Hong Fan, Haichun Yang, Agnes B. Fogo, Roy Zent, Raymond C. Harris, Matthew D. Breyer, Chuan‐Ming Hao · 发表于：Journal of Clinical Investigation · 年份：2010 · DOI：10.1172/jci41563 · 被引用次数：318 · 研究领域：Sirtuins and Resveratrol in Medicine、Heme Oxygenase-1 and Carbon Monoxide、Autophagy in Disease and Therapy

Sirtuin 1 (Sirt1) is a NAD+-dependent deacetylase that exerts many of the pleiotropic effects of oxidative metabolism. Due to local hypoxia and hypertonicity, the renal medulla is subject to extreme oxidative stress. Here, we set out to investigate the role of Sirt1 in the kidney. Our initial analysis indicated that it was abundantly expressed in mouse renal medullary interstitial cells in vivo. Knocking down Sirt1 expression in primary mouse renal medullary interstitial cells substantially reduced cellular resistance to oxidative stress, while pharmacologic Sirt1 activation using either resveratrol or SRT2183 improved cell survival in response to oxidative stress. The unilateral ureteral obstruction (UUO) model of kidney injury induced markedly more renal apoptosis and fibrosis in Sirt1+/- mice than in wild-type controls, while pharmacologic Sirt1 activation substantially attenuated apoptosis and fibrosis in wild-type mice. Moreover, Sirt1 deficiency attenuated oxidative stress-induced COX2 expression in cultured mouse renal medullary interstitial cells, and Sirt1+/- mice displayed reduced UUO-induced COX2 expression in vivo. Conversely, Sirt1 activation increased renal medullary interstitial cell COX2 expression both in vitro and in vivo. Furthermore, exogenous PGE2 markedly reduced apoptosis in Sirt1-deficient renal medullary interstitial cells following oxidative stress. Taken together, these results identify Sirt1 as an important protective factor for mouse renal medulla...