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Protective Effect of EX-527 Against High-Fat Diet-Induced Diabetic Nephropathy in Zucker Rats

Protective Effect of EX-527 Against High-Fat Diet-Induced Diabetic Nephropathy in Zucker Rats

Amit Kundu, Sachan Richa, Prasanta Dey, Kyeong Seok Kim, Ji Yeon Son, Hae Ri Kim, Seok-Yong Lee, Byung-Hoon Lee, Kwang Youl Lee, Sam Kacew, Byung Mu Lee, Hyung Sik Kim

Toxicol Appl Pharmacol. 2020 Mar 1;390:114899.

PMID: 31981641

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP49843983-A	EX-527		49843-98-3	Price

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