title: SIRT1 activator ameliorates the renal tubular injury induced by hyperglycemia in vivo and in vitro via inhibiting apoptosis.
abstract: We aimed to explore the role of SIRT1 in apoptosis in human kidney proximal tubule epithelial (HK-2) cells, and to determine whether resveratrol (RSV, a SIRT1 activator) could ameliorate apoptosis in rats with streptozotocin-induced diabetes mellitus (DM) and/or in high glucose (HG, 30mM) - stimulated HK-2 cells. Rats were distributed randomly into three groups: 1) control group, 2) DM group, and 3) DM with RSV group (DM+RSV; rats treated with 30mg/kg/d of RSV for 16 weeks). The physical, biochemical, and morphological parameters were then examined. Additionally, the deacetylase activity of SIRT1, and the expression levels of SIRT1 and of representative apoptosis markers, such as p53, acetylated p53, cleaved caspase-3, caspase-9, and cleaved PARP, were measured. HK-2 cells were stimulated by HG for different lengths of time to study the effect of HG on apoptosis. HK-2 cells were treated with or without RSV (25μM) to investigate if RSV has a protective effect on HG-induced apoptosis. A gene-specific small interfering RNA against SIRT1 was used to study the role of SIRT1 in apoptosis. More apoptosis was found in the DM rats than in the control rats. Similarly, the expression levels of cleaved caspase-3, cleaved PARP, and acetylated p53 were significantly higher, and the level of SIRT1 was significantly lower, in the HK-2 cells that were cultured under HG conditions than those in the HK-2 cells that were cultured under low glucose (5.5mM) conditions. Notably, treatment with RSV lessened the HG-induced changes in the levels of apoptosis indicators, and this inhibition of HG-induced apoptosis in HK-2 cells by RSV treatment was abolished by SIRT1 silencing. Our study showed that hyperglycemia contributes to apoptosis in rat kidney and HK-2 cells. SIRT1 activation by RSV can reduce urinary albumin excretion and proximal tubule epithelial apoptosis both in vitro and in vivo. Based on our study, SIRT1/p53 axis played an important role in the hyperglycemia induced apoptosis. These findings indicated that the increased expression of SIRT1, mediated by RSV, is a possible mechanism by which RSV prevents renal tubular injury in diabetic nephropathy (DN). So RSV has great clinical significance and could provide the basis for the new way to effective treatment to contain the morbidity and mortality associated with DN.
authors.affiliation: Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, China.
authors.forename: Xue-Ling
authors.initials: XL
authors.lastname: Wang
authors.affiliation: Room for Hemodialysis, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China.
authors.forename: Li-Yan
authors.initials: LY
authors.lastname: Wu
authors.affiliation: Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, China.
authors.forename: Long
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, China.
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Sun
authors.affiliation: Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, China.
authors.forename: Hai-Ying
authors.initials: HY
authors.lastname: Liu
authors.affiliation: Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, China. Electronic address: gangliu@sdu.edu.cn.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, China. Electronic address: guangj@sdu.edu.cn.
authors.forename: Guang-Ju
authors.initials: GJ
authors.lastname: Guan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D020868:Gene Silencing / Q000187:drug effects; D005947:Glucose / Q000633:toxicity; D006801:Humans; D006943:Hyperglycemia / Q000150:complications*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000473:pathology*; D017208:Rats, Wistar; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*; D013311:Streptozocin
chemical_list: D013267:Stilbenes; D013311:Streptozocin; D056564:Sirtuin 1; D005947:Glucose; D000077185:Resveratrol
keywords: Apoptosis; Diabetic nephropathy; HK-2 cells; Resveratrol; SIRT1; p53