Tenovin-1 Ameliorates Renal Fibrosis in High-Fat-Diet-Induced Diabetic Nephropathy via Antioxidant and Anti-Inflammatory Pathways

Abstract

High-fat diet (HFD)-induced obesity has been involved in the development of diabetic nephropathy (DN). Tenovin-1, a potent selective SIRT1/2 inhibitor, regulates various target proteins. The present study evaluated the protective effect of Tenovin-1 against renal fibrosis in HFD-induced Zucker diabetic fatty (ZDF) rats. Rats were fed a normal chow diet or HFD. Tenovin-1 (45 mg/kg) administered to HFD-fed rats decreased inflammatory cytokine expression in the serum of the rats. The antioxidant status and oxidative damage to lipids or DNA were significantly restored by Tenovin-1. Additionally, Tenovin-1 reduced the levels of blood urea nitrogen (BUN), serum creatinine (sCr), microalbumin, and urinary protein-based biomarkers in the urine of HFD-fed rats. The abnormal architecture of the kidney and pancreas was restored by Tenovin-1 administration. Tenovin-1 also reduced apoptosis in the kidneys of the HFD-fed rats and HG-treated NRK-52E cells. It significantly lowered the levels of ECM proteins in the kidneys of HFD-fed rats and HG-treated NRK-52E cells. Additionally, Tenovin-1 markedly reduced claudin-1, SIRT1, and SIRT2, but increased SIRT3 and SIRT4 in HFD-fed rats and NRK-52E cells treated with HG. Furthermore, Tenovin-1 altered epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor-β (PDGFR-β), and signal transducer and activator of transcription 3 (STAT3) levels in the kidneys of HFD-fed rats. Conclusively, this study shows that Tenovin-1 can be a potential candidate drug for the treatment of HFD-induced renal fibrosis, in vivo and in vitro models.

Translation Animal Models of Diabetic Kidney Disease: Biochemical and Histological Phenotypes, Advantages and Limitations

“… 127–130 In addition, HFD (60% kcal fat) can exacerbate nephropathy in these rats and shorten the experimental duration. 130 , 131 …”

Tenovin-1, a Selective SIRT1/2 Inhibitor, Attenuates High-fat Diet-induced Hepatic Fibrosis via Inhibition of HSC Activation in ZDF Rats

“…Recently, Tenovin-1 has also been proposed as a potential treatment option for COVID-19 infection 21 . The reno-protective effect of Tenovin-1 has also been studied in rats with diabetic nephropathy, which showed its positive antifibrotic effects 22 . However, the effect of Tenovin-1 on NAFLD and hepatic fibrosis remains unclear.…”