Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung 204, Taiwan.
Department of Anatomy, School of Medicine, China Medical University, Taichung 404, Taiwan.
Int J Mol Sci. 2020 Sep 15;21(18):6766. doi: 10.3390/ijms21186766.
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.
衰老的肾脏易发生肾小球硬化，肾功能呈可测量性下降。有证据表明，肾脏和全身 klotho 和 SIRT1（SIRT1）的缺乏会加重外源性应激引起的肾脏损伤。本研究旨在探讨白藜芦醇是否会减轻伴刀豆球蛋白 A（Con A）诱导的老年小鼠肾脏氧化应激和晚期肾小球硬化。雄性 C57BL/6 老年小鼠在单次尾静脉注射 Con A（20mg/kg）前，经口给予白藜芦醇（30mg/kg）7 次（12 小时间隔）。评估了血浆和尿中肾脏损伤标志物的水平。测量了肾脏组织病理学、肾脏参数和氧化应激水平。此外，在 25µM 白藜芦醇预处理后，用 20µg/mL Con A 处理的小鼠肾脏系膜细胞中 klotho 下调。与 Con A 处理的老年小鼠相比，尿白蛋白/肌酐比值、血尿素氮、肾小球系膜基质扩张、肾小管间质纤维化以及肾脏中α-平滑肌肌动蛋白、转化生长因子-β、纤维连接蛋白、III 型前胶原肽和胶原 I 的水平显著增加。衰老小鼠的肾脏在 Con A 攻击后还显示出明显增加的 8-羟基脱氧鸟苷（8-OH-dG）和活性氧（ROS）水平，超氧化物歧化酶活性和谷胱甘肽、klotho 和 SIRT1 的水平降低。此外，在肾脏系膜细胞中，klotho 沉默消除了白藜芦醇对 Con A 介导的氧化应激指标升高和肾小球硬化相关因子表达的影响。这些发现表明，白藜芦醇通过 SIRT1 介导的 klotho 表达，防止 Con A 诱导的老年小鼠晚期肾小球硬化，改善肾脏氧化应激。
