Antifibrotic effects of KS370G, a caffeamide derivative, in renal ischemia-reperfusion injured mice and renal tubular epithelial cells

Accumulating evidence suggests that renal tubulointerstitial fibrosis is a main cause of end-stage renal disease. Clinically, there are no beneficial treatments that can effectively reverse the progressive loss of renal functions. Caffeic acid phenethyl ester is a natural phenolic antifibrotic agent, but rapid decomposition by an esterase leads to its low bioavailability. In this study, we evaluated the effects of KS370G, a caffeic acid phenylethyl amide, on murine renal fibrosis induced by unilateral renal ischemia-reperfusion injury (IRI) and in TGF-β(1) stimulated renal tubular epithelial cells (NRK52E and HK-2). In the animal model, renal fibrosis was evaluated at 14 days post-operation. Immediately following the operation, KS370G (10 mg/kg) was administered by oral gavage once a day. Our results show that KS370G markedly attenuates collagen deposition and inhibits an IRI-induced increase of fibronectin, vimentin, α-SMA and TGF-β(1) expression and plasma TGF-β(1) levels in the mouse kidney. Furthermore, KS370G reverses TGF-β(1)-induced downregulation of E-cadherin and upregulation of α-SMA and also decreases the expression of fibronectin, collagen I and PAI-1 and inhibits TGF-β(1)-induced phosphorylation of Smad2/3. These findings show the beneficial effects of KS370G on renal fibrosis in vivo and in vitro with the possible mechanism being the inhibition of the Smad2/3 signaling pathway.