Wang Xueling, Meng Linghang, Zhao Long, Wang Zengfu, Liu Haiying, Liu Gang, Guan Guangju
Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, China.
Anesthesia Department, Shengli Oilfield Central Hospital, Dongying, Shandong, China.
Diabetes Res Clin Pract. 2017 Apr;126:172-181. doi: 10.1016/j.diabres.2016.12.005. Epub 2016 Dec 18.
Oxidative stress plays an important role in the development and progression of diabetic nephropathy (DN). We aimed to investigate if resveratrol (RSV) could ameliorate hyperglycemia-induced oxidative stress in renal tubules via modulating the SIRT1/FOXO3a pathway.
The effects of RSV on diabetes rats were assessed by periodic acid-Schiff, Masson staining, immunohistochemistry, and western blot analyses. Additionally, oxidative indicators (such as catalase, superoxide dismutase, reactive oxygen species, and malondialdehyde), the deacetylase activity of SIRT1 and protein expressions of SIRT1, FOXO3a, and acetylated-FOXO3a were measured. These indicators were similarly evaluated in an in vitro study. Furthermore, the silencing of SIRT1 was used to confirm its role in the resistance to oxidative stress and the relationship between SIRT1 and FOXO3a in vitro.
After 16weeks of RSV treatment, the renal function and glomerulosclerosis of rats with DN was dramatically ameliorated. RSV treatment increased SIRT1 deacetylase activity, subsequently decreasing the expression of acetylated-FOXO3a and inhibiting the oxidative stress caused by hyperglycemia both in vivo and in vitro. The silencing of SIRT1 in HK-2 cells aggravated the high glucose-induced oxidative stress and overexpression of acetylated-FOXO3a; RSV treatment failed to protect against these effects.
RSV modulates the SIRT1/FOXO3a pathway by increasing SIRT1 deacetylase activity, subsequently ameliorating hyperglycemia-induced renal tubular oxidative stress damage. This mechanism provides the basis for a new approach to developing an effective DN treatment, which is of great clinical significance for reducing the morbidity and mortality associated with DN.
氧化应激在糖尿病肾病（DN）的发生和发展中起重要作用。我们旨在研究白藜芦醇（RSV）是否可以通过调节SIRT1/FOXO3a信号通路来改善高血糖诱导的肾小管氧化应激。
通过过碘酸希夫染色、Masson染色、免疫组织化学和蛋白质印迹分析评估RSV对糖尿病大鼠的影响。此外，检测氧化指标（如过氧化氢酶、超氧化物歧化酶、活性氧和丙二醛）、SIRT1的脱乙酰酶活性以及SIRT1、FOXO3a和乙酰化FOXO3a的蛋白表达。在体外研究中对这些指标进行类似评估。此外，通过沉默SIRT1来证实其在体外对氧化应激的抵抗作用以及SIRT1与FOXO3a之间的关系。
RSV治疗16周后，DN大鼠的肾功能和肾小球硬化得到显著改善。RSV治疗增加了SIRT1脱乙酰酶活性，随后降低了乙酰化FOXO3a的表达，并在体内和体外抑制了高血糖引起的氧化应激。HK-2细胞中SIRT1的沉默加剧了高糖诱导的氧化应激和乙酰化FOXO3a的过表达；RSV治疗未能预防这些效应。
RSV通过增加SIRT1脱乙酰酶活性来调节SIRT1/FOXO3a信号通路，随后改善高血糖诱导的肾小管氧化应激损伤。这一机制为开发有效的DN治疗新方法提供了依据，对降低DN的发病率和死亡率具有重要临床意义。
