Nephrology Division, Vanderbilt University Medical Center School of Medicine, Nashville, Tennessee 37232, USA.
J Clin Invest. 2010 Apr;120(4):1056-68. doi: 10.1172/JCI41563. Epub 2010 Mar 24.
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 medullary interstitial cells following oxidative stress and suggest that the protective function of Sirt1 is partly attributable to its regulation of COX2 induction. We therefore suggest that Sirt1 provides a potential therapeutic target to minimize renal medullary cell damage following oxidative stress.
Sirtuin 1（Sirt1）是一种 NAD+-依赖性去乙酰化酶，它发挥氧化代谢的许多多效性作用。由于局部缺氧和高渗，肾髓质受到极端的氧化应激。在这里，我们着手研究 Sirt1 在肾脏中的作用。我们的初步分析表明，它在体内大量表达于小鼠肾髓质间质细胞中。在原代小鼠肾髓质间质细胞中敲低 Sirt1 表达会显著降低细胞对氧化应激的抵抗力，而使用白藜芦醇或 SRT2183 进行药理学 Sirt1 激活可改善细胞对氧化应激的存活能力。单侧输尿管梗阻（UUO）模型诱导的肾损伤在 Sirt1+/-小鼠中比野生型对照小鼠引起更明显的肾细胞凋亡和纤维化，而药理学 Sirt1 激活在野生型小鼠中显著减轻了细胞凋亡和纤维化。此外，Sirt1 缺乏可减轻培养的小鼠肾髓质间质细胞中氧化应激诱导的 COX2 表达，并且 Sirt1+/-小鼠体内 UUO 诱导的 COX2 表达减少。相反，Sirt1 激活可增加体外和体内肾髓质间质细胞 COX2 的表达。此外，外源性 PGE2 可显著减少氧化应激后 Sirt1 缺陷的肾髓质间质细胞中的细胞凋亡。总之，这些结果表明 Sirt1 是氧化应激后小鼠肾髓质间质细胞的重要保护因子，并表明 Sirt1 的保护功能部分归因于其对 COX2 诱导的调节。因此，我们认为 Sirt1 为减少氧化应激后肾髓质细胞损伤提供了一个潜在的治疗靶点。
