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：

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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。