当前位置: X-MOL 学术Toxicol. Appl. Pharmacol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Protective effect of EX-527 against high-fat diet-induced diabetic nephropathy in Zucker rats.
Toxicology and Applied Pharmacology ( IF 3.3 ) Pub Date : 2020-01-22 , DOI: 10.1016/j.taap.2020.114899
Amit Kundu 1 , Sachan Richa 1 , Prasanta Dey 1 , Kyeong Seok Kim 1 , Ji Yeon Son 1 , Hae Ri Kim 1 , Seok-Yong Lee 1 , Byung-Hoon Lee 2 , Kwang Youl Lee 3 , Sam Kacew 4 , Byung Mu Lee 1 , Hyung Sik Kim 1
Affiliation  

High-fat diet (HFD)-induced obesity is implicated in diabetic nephropathy (DN). EX-527, a selective Sirtuin 1 (SIRT1) inhibitor, has multiple biological functions; however, its protective effect against DN is yet to be properly understood. This study was aimed to explore the protective effect of EX-527 against DN in HFD-induced diabetic Zucker (ZDF) rats. After 21 weeks of continually feeding HFD to the rats, the apparent characteristics of progressive DN were observed, which included an increase in kidney weight (~160%), hyperglycemia, oxidative stress, and inflammatory cytokines, and subsequent renal cell damage. However, the administration of EX-527 for 10 weeks significantly reduced the blood glucose concentration and kidney weight (~59%). Furthermore, EX-527 significantly reduced the serum concentration of transforming growth factor-β1 (49%), interleukin (IL)-1β (52%), and IL-6 in the HFD-fed rats. Overall, the antioxidant activities significantly increased, and oxidative damage to lipids or DNA was suppressed. Particularly, EX-527 significantly reduced blood urea nitrogen (81%), serum creatinine (71%), microalbumin (43%), and urinary excretion of protein-based biomarkers. Histopathological examination revealed expansion of the extracellular mesangial matrix and suppression of glomerulosclerosis following EX-527 administration. EX-527 downregulated the expression of α-SMA (~64%), TGF-β (25%), vimentin, α-tubulin, fibronectin, and collagen-1 in the kidneys of the HFD-fed rats. Additionally, EX-527 substantially reduced claudin-1 and SIRT1 expression, but increased the expression of SIRT3 in the kidneys of the HFD-fed rats. EX-527 also inhibited the growth factor receptors, including EGFR, PDGFR-β, and STAT3, which are responsible for the anti-fibrotic effect of SIRT-1. Therefore, the administration of EX-527 protects against HFD-induced DN.

中文翻译:

EX-527对高脂饮食诱导的Zucker大鼠糖尿病性肾病的保护作用。

高脂饮食(HFD)引起的肥胖与糖尿病肾病(DN)有关。EX-527是一种选择性Sirtuin 1(SIRT1)抑制剂,具有多种生物学功能。但是,它对DN的保护作用尚待适当了解。这项研究旨在探讨EX-527对HFD诱导的糖尿病Zucker(ZDF)大鼠的DN的保护作用。在连续向大鼠喂食HFD 21周后,观察到进行性DN的明显特征,包括肾脏重量增加(〜160%),高血糖,氧化应激和炎性细胞因子,以及随后的肾细胞损害。但是,EX-527给药10周可显着降低血糖浓度和肾脏重量(〜59%)。此外,EX-527显着降低了转化生长因子-β1的血清浓度(49%),HFD喂养的大鼠中白介素(IL)-1β(52%)和IL-6。总体而言,抗氧化剂活性显着增加,并且抑制了脂质或DNA的氧化损伤。特别是,EX-527显着降低了血液尿素氮(81%),血清肌酐(71%),微量白蛋白(43%)和基于蛋白质的生物标志物的尿排泄。组织病理学检查显示EX-527给药后细胞外系膜基质的扩张和肾小球硬化的抑制。EX-527下调了HFD喂养大鼠肾脏中α-SMA(〜64%),TGF-β(25%),波形蛋白,α-微管蛋白,纤连蛋白和胶原蛋白1的表达。另外,EX-527显着降低了HFD喂养大鼠肾脏中claudin-1和SIRT1的表达,但增加了SIRT3的表达。EX-527也抑制生长因子受体,包括EGFR,PDGFR-β和STAT3,它们负责SIRT-1的抗纤维化作用。因此,EX-527的使用可防止HFD诱导的DN。
更新日期:2020-01-22
down
wechat
bug