Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK-SIRT1-PGC1α axis in db/db mice
Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK-SIRT1-PGC1α axis in db/db mice
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DOI：
10.1007/s00125-012-2747-2
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发表时间：
2013-01-01
期刊：
影响因子：
8.2
通讯作者：
Park, C. W.
中科院分区：
文献类型：
--
作者：
Kim, M. Y.;Lim, J. H.;Park, C. W.
白藜芦醇的许多作用与AMP激活的蛋白激酶(AMPK)、沉默的信息调节因子T1(SIRT1)和过氧化物酶体增殖物激活受体(PPAR)γ共激活因子1α(PGC-1α)的激活是一致的，它们在调节血脂和血糖的动态平衡和控制氧化应激中发挥着关键作用。本研究以雄性C57BLKS/J db/m和db/db小鼠为研究对象，观察白藜芦醇对2型糖尿病小鼠肾脏的保护作用。白藜芦醇从8周大的糖尿病小鼠和非糖尿病小鼠开始，通过灌胃给予白藜芦醇，为期12周。白藜芦醇改善肾小球基质扩张和炎症。白藜芦醇还降低了肾脏的NEFA和三酰甘油含量，这一作用与增加AMPK的磷酸化、激活SIRT1-PGC-1α信号和关键的下游效应因子PPARα-雌激素相关受体(ERR)-1α-固醇调节元件结合蛋白1(SREBP1)有关。此外，白藜芦醇还可降低磷脂酰肌醇-3激酶(PI3K)-Akt的磷酸化和O类叉头盒(FOXO)3a的磷酸化，导致B细胞白血病/淋巴瘤2(Bcl2)相关的X蛋白(Bax)减少，bcl2、超氧化物歧化酶(SOD)1和SOD2的产生增加。因此，白藜芦醇逆转了肾脏细胞凋亡和氧化应激的增加，反映在肾脏8-羟基脱氧鸟苷(8-OH-DG)、尿8-OH-DG和异前列腺素浓度上。白藜芦醇通过AMPK的磷酸化和SIRT1-PGC-1α信号及其下游效应PPARα-ERR-1α-SREBP1的激活来预防高糖诱导的系膜细胞的氧化应激和凋亡。结果表明，白藜芦醇通过AMPK的磷酸化和SIRT1-PGC-1α信号的激活来预防db/db小鼠的糖尿病肾病，这似乎可以防止肾脏的脂毒性相关的细胞凋亡和氧化应激。
Many of the effects of resveratrol are consistent with the activation of AMP-activated protein kinase (AMPK), silent information regulator T1 (SIRT1) and peroxisome proliferator-activated receptor (PPAR)gamma co-activator 1 alpha (PGC-1 alpha), which play key roles in the regulation of lipid and glucose homeostasis, and in the control of oxidative stress. We investigated whether resveratrol has protective effects on the kidney in type 2 diabetes.Four groups of male C57BLKS/J db/m and db/db mice were used in this study. Resveratrol was administered via gavage to diabetic and non-diabetic mice, starting at 8 weeks of age, for 12 weeks.The db/db mice treated with resveratrol had decreased albuminuria. Resveratrol ameliorated glomerular matrix expansion and inflammation. Resveratrol also lowered the NEFA and triacylglycerol content of the kidney, and this action was related to increases in the phosphorylation of AMPK and the activation of SIRT1-PGC-1 alpha signalling and of the key downstream effectors, the PPAR alpha-oestrogen-related receptor (ERR)-1 alpha-sterol regulatory element-binding protein 1 (SREBP1). Furthermore, resveratrol decreased the activity of phosphatidylinositol-3 kinase (PI3K)-Akt phosphorylation and class O forkhead box (FOXO)3a phosphorylation, which resulted in a decrease in B cell leukaemia/lymphoma 2 (BCL-2)-associated X protein (BAX) and increases in BCL-2, superoxide dismutase (SOD)1 and SOD2 production. Consequently, resveratrol reversed the increase in renal apoptotic cells and oxidative stress, as reflected by renal 8-hydroxy-deoxyguanosine (8-OH-dG), urinary 8-OH-dG and isoprostane concentrations. Resveratrol prevented high-glucose-induced oxidative stress and apoptosis in cultured mesangial cells through the phosphorylation of AMPK and activation of SIRT1-PGC-1 alpha signalling and the downstream effectors, PPAR alpha-ERR-1 alpha-SREBP1.The results suggest that resveratrol prevents diabetic nephropathy in db/db mice by the phosphorylation of AMPK and activation of SIRT1-PGC-1 alpha signalling, which appear to prevent lipotoxicity-related apoptosis and oxidative stress in the kidney.