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The Sirt1 activator, SRT1720, attenuates renal fibrosis by inhibiting CTGF and oxidative stress

The transforming growth factor-β1 (TGF-β1)/connective tissue growth factor (CTGF) pathway plays an important role in the pathogenesis and progression of chronic kidney disease. Oxidative stress is also involved in TGF-β1 signalling. Sirtuin 1 (Sirt1) exerts a number of pleiotropic effects, protecting against renal disease, including inhibiting fibrosis and oxidative metabolism. In this study, we investigated the role of the Sirt1 activator, SRT1720, in unilateral ureteral obstruction (UUO)-induced tubulointerstitial fibrosis and aimed to determine whether this role depends on the inhibition of oxidative stress and the TGF-β1/CTGF pathway. Renal fibrosis was induced by UUO in CD1 mice. SRT1720 (100 mg/kg) was administered by intraperitoneal injection for 3 days prior to UUO and this was continued for 7 days following UUO. Histological changes were examined by Masson's trichrome staining. The expression of fibrosis-related factors was evaluated by immunohistochemistry, western blot analysis and RT-qPCR. Apoptosis was also examined. We also examined the superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GPx) and reduced glutathione (GSH) levels. UUO induced renal fibrosis and apoptosis and decreased Sirt1 expression. The administration of SRT1720 increased the Sirt1 levels and partially attenuated UUO-induced renal fibrosis and apoptosis. Furthermore, SRT1720 attenuated the levels of oxidative stress (it decreased the MDA levels, and increased the SOD, GPx and GSH levels), which suggests that it protected the cells against ROS-induced damage. Moreover, SRT1720effectively inhibited the levels of TGF-β1/CTGF induced by UUO. On the whole, these findings indicate that the Sirt1 activator, SRT1720, exerts protective effects against UUO-induced tubulointerstitial fibrosis. The mechanisms of action of SRT1720 may include, at least in part, the suppression of renal oxidative stress and the TGF-β1/CTGF signalling pathway. The Sirt1 activator may therefore be prove to be a potent therapeutic agent for the treatment of fibrotic kidney disease.

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S1129 SRT1720 HCl SRT1720 HCl is a selective SIRT1 activator with EC50 of 0.16 μM in a cell-free assay, but is >230-fold less potent for SIRT2 and SIRT3. SRT1720 induces autophagy.

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Sirtuin