Resveratrol Pretreatment Ameliorates Concanavalin A-Induced Advanced Renal Glomerulosclerosis in Aged Mice through Upregulation of Sirtuin 1-Mediated Klotho Expression.
Resveratrol Pretreatment Ameliorates Concanavalin A-Induced Advanced Renal Glomerulosclerosis in Aged Mice through Upregulation of Sirtuin 1-Mediated Klotho Expression.
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DOI：
10.3390/ijms21186766
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发表时间：
2020-09-15
影响因子：
5.6
通讯作者：
Chen SY
中科院分区：
文献类型：
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作者：
Chen CC;Chang ZY;Tsai FJ;Chen SY
肾脏老化的特点是对肾小球硬化的易感性增加，肾功能明显下降。有证据表明，肾脏和全身klotho和sirtuin1(SIRT1)缺乏会加重外源性应激引起的肾脏损伤。本研究的目的是探讨白藜芦醇是否能减轻刀豆蛋白A(ConA)诱导的老年小鼠肾脏氧化应激和进展性肾小球硬化。老年雄性C57BL/6小鼠在单次尾静脉注射刀豆蛋白A(20 mg/kg)前，给予白藜芦醇(30 mg/kg)灌胃7次(间隔12h)。测定血、尿中肾损害标志物水平。测量肾脏组织病理学、肾脏参数和氧化应激水平。此外，25µM白藜芦醇和20µg/mLConA处理组小鼠肾小球系膜细胞Klotho表达下调，尿白蛋白/肌酐比值、血尿素氮、肾小球系膜基质扩张、肾小管间质纤维化、肾脏α-平滑肌肌动蛋白、转化生长因子β、纤维连接蛋白、III型前胶原肽和I型胶原水平显著升高。衰老小鼠肾脏8-羟基脱氧鸟苷(8-OH-DG)和活性氧(ROS)水平显著升高，超氧化物歧化酶活性降低，谷胱甘肽、Klotho和SIRT1水平降低。此外，在肾小球系膜细胞中，Klotho沉默取消了白藜芦醇对ConA介导的氧化应激指数和肾小球硬化相关因子表达的影响。这些发现表明，白藜芦醇可通过SIRT1介导的Klotho表达来减轻肾脏氧化应激，从而对ConA诱导的老年小鼠晚期肾小球硬化具有保护作用。
Aging kidneys are characterized by an increased vulnerability to glomerulosclerosis and a measurable decline in renal function. Evidence suggests that renal and systemic klotho and sirtuin 1 (SIRT1) deficiencies worsen kidney damage induced by exogenous stresses. The aim of this study was to explore whether resveratrol would attenuate concanavalin A (Con A)-induced renal oxidative stress and advanced glomerulosclerosis in aged mice. Aged male C57BL/6 mice were treated orally with resveratrol (30 mg/kg) seven times (12 h intervals) prior to the administration of a single tail-vein injection of Con A (20 mg/kg). The plasma and urinary levels of kidney damage markers were evaluated. The kidney histopathology, renal parameters, and oxidative stress levels were measured. Furthermore, klotho was downregulated in mouse kidney mesangial cells that were pretreated with 25 µM resveratrol followed by 20 µg/mL Con A. The urinary albumin/creatinine ratio, blood urea nitrogen, kidney mesangial matrix expansion, tubulointerstitial fibrosis, and renal levels of α-smooth muscle actin, transforming growth factor beta, fibronectin, procollagen III propeptide, and collagen type I significantly increased in Con A-treated aged mice. Aged mice kidneys also showed markedly increased levels of 8-hydroxydeoxyguanosine (8-OH-dG) and reactive oxygen species (ROS), with reduced superoxide dismutase activity and levels of glutathione, klotho, and SIRT1 after Con A challenge. Furthermore, in kidney mesangial cells, klotho silencing abolished the effects of resveratrol on the Con A-mediated elevation of the indices of oxidative stress and the expression of glomerulosclerosis-related factors. These findings suggest that resveratrol protects against Con A-induced advanced glomerulosclerosis in aged mice, ameliorating renal oxidative stress via the SIRT1-mediated klotho expression.