| Summary: | 博士 === 國立臺灣大學 === 藥理學研究所 === 103 === 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, a major component of propolis, is distributed wildly in nature and has anti-diabetic and anti-fibrotic effects. However, rapid decomposition by an esterase leads to its low bioavailability in vivo. In this study, we evaluated the effects of KS370G, a synthetic caffeamide derivative, on murine renal fibrosis induced by unilateral renal ischemia-reperfusion injury (IRI) and unilateral ureteral obstruction (UUO), and on TGF-β1 stimulated renal tubular epithelial cells (HK-2 and NRK52E) signaling.
In the animal models, 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. In the IRI model, our results show that KS370G markedly attenuated collagen deposition and inhibits an IRI-induced increase of fibronectin, vimentin, α-SMA and TGF-β1 expression in the mouse kidney and plasma TGF-β1. In the UUO model, our results show that KS370G significantly attenuated collagen deposition in the obstructed kidney and inhibited UUO-induced renal fibrosis markers expression, including fibronectin, type I collagen, vimentin, and α-smooth muscle actin (α-SMA). KS370G significantly lowered the expression of renal inflammatory chemokines/adhesion molecules and monocyte cells marker (MCP-1, VCAM-1, ICAM-1 and CD11b). KS370G also reduced renal malondialdehyde (MDA) levels and reversed the expression of renal antioxidant enzymes (SOD and catalase) after UUO. Furthermore, KS370G significantly inhibited UUO-induced elevated plasma Ang II and TGF-β1 levels, TGF-β1 protein expression and Smad3 phosphorylation.
In vitro study, we used human (HK-2) and non-human (NRK52E) renal epithelial cell lines. Our results showed that KS370G reverses TGF-β1-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-β1-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 through the inhibition of Ang II, TGF-β and Smad3 signaling pathways.
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