Resveratrol improves left ventricular remodeling in chronic kidney disease via Sirt1‐mediated regulation of FoxO1 activity and MnSOD expression

Abstract

Left ventricular remodeling commonly complicates end-stage renal disease following chronic kidney disease (CKD). This study investigated the therapeutic efficacy of resveratrol (RSV), a polyphenolic compound, on left ventricular remodeling in subtotal nephrectomy rats and sought to uncover the underlying molecular mechanisms. Subtotal nephrectomy caused renal dysfunction, such as gradual increases in serum creatinine and blood urea nitrogen, glomerular sclerosis, and tubulointerstitial fibrosis. In addition, subtotal nephrectomy also resulted in significant increases in myocyte cross-sectional area, interstitial and perivascular fibrosis, and left ventricular dilatation. All these detrimental effects were alleviated in the presence of RSV. Mechanistically, RSV treatment led to the upregulation of manganese-containing superoxide dismutase (MnSOD) in the heart. Coimmunoprecipitation studies showed that silent information regulator 1 (Sirt1) bound forkhead box protein O1 (FoxO1) and thus reduced acetylated FoxO1. RSV strengthened this interaction between Sirt1 and FoxO1. Loss of one allele of Sirt1 aggravated renal damage, myocyte hypertrophy, and interstitial fibrosis in nephrectomized mice. Taken together, our data show that Sirt1 is an important mediator for the protective roles of RSV on renal and heart damage in CKD rodent model, and FoxO1 and MnSOD are likely downstream targets of Sirt1. Therefore, Sirt1 might be a potential therapeutic target for the treatment of left ventricular remodeling caused by CKD.