Department of Nephrology, State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853, People's Republic of China.
Mech Ageing Dev. 2012 Jun;133(6):387-400. doi: 10.1016/j.mad.2012.04.005. Epub 2012 May 4.
The mTOR deregulation has a role in chronic kidney disease including diabetic nephropathy. SIRT1 is an important participant in renal cytoprotective responses to aging and stress. However, whether both mTOR and SIRT1 are involved in high glucose-inducing mesangial cells (MCs) senescence still remains to be explored. Hence we investigate the potential functional interrelationship between these two proteins in high glucose-inducing MCs senescence. High glucose increased mTOR expression and activity, but decreased SIRT1 expression and activity. The level of mTOR was increased significantly, while the SIRT1 expression and activity was declined significantly with serial cell culture passage. The siRNA-SIRT1 and nicotinamide promoted MCs senescence. NAD or resveratrol arrested high glucose-inducing MCs senescence. Meanwhile, the effects of NAD or resveratrol on high glucose-inducing MCs senescence were also completely blocked by SiRNA-SIRT1. Rapamycin arrested MCs senescence induced by high glucose and prevented MCs senescence with serial cell culture passage, and meanwhile increased the SIRT1 expression and activity. Moreover, the effects of rapamycin on MCs senescence induced by high glucose were also completely blocked by treating cells with niacinamide or siRNA-SIRT1. These findings provide support for the hypothesis that SIRT1 is required for the effects of rapamycin on high glucose-inducing MCs senescence.
mTOR 失调在包括糖尿病肾病在内的慢性肾脏病中起作用。SIRT1 是肾脏对衰老和应激的细胞保护反应的重要参与者。然而，mTOR 和 SIRT1 是否都参与高糖诱导的系膜细胞（MC）衰老仍有待探讨。因此，我们研究了这两种蛋白在高糖诱导的 MC 衰老中的潜在功能相互关系。高糖增加了 mTOR 的表达和活性，但降低了 SIRT1 的表达和活性。mTOR 的水平显著增加，而 SIRT1 的表达和活性随着细胞传代培养而显著下降。siRNA-SIRT1 和烟酰胺促进 MC 衰老。NAD 或白藜芦醇阻止高糖诱导的 MC 衰老。同时，siRNA-SIRT1 完全阻断了 NAD 或白藜芦醇对高糖诱导的 MC 衰老的作用。雷帕霉素阻止高糖诱导的 MC 衰老，并防止细胞传代培养过程中的 MC 衰老，同时增加 SIRT1 的表达和活性。此外，雷帕霉素对高糖诱导的 MC 衰老的作用也被烟酰胺或 siRNA-SIRT1 处理完全阻断。这些发现为 SIRT1 是雷帕霉素对高糖诱导的 MC 衰老作用所必需的假说提供了支持。
