Abstract
Renal fibrosis is a common pathway of virtually all progressive kidney diseases. Osthole (OST, 7-Methoxy-8-(3-methylbut-2-enyl)-2-chromenone), a derivative of coumarin mainly found in plants of the Apiaceae family, has shown inhibitory effects on inflammation, oxidative stress, fibrosis and tumor progression. The present study investigated whether OST mediates its effect via suppressing fibroblast activation and epithelial-mesenchymal transition (EMT) in unilateral ureteral obstruction (UUO)-induced renal fibrosis in mice. Herein, we found that OST inhibited fibroblast activation in a dose-dependent manner by inhibiting the transforming growth factor-β1 (TGFβ1)-Smad pathway. OST also blocked fibroblast proliferation by reducing DNA synthesis and downregulating the expressions of proliferation- and cell cycle-related proteins including proliferating cell nuclear antigen (PCNA), CyclinD1 and p21 Waf1/Cip1. Meanwhile, in the murine model of renal interstitial fibrosis induced by UUO, myofibroblast activation with increased expression of α-smooth muscle actin (α-SMA) and proliferation were attenuated by OST treatment. Additionally, we provided in vivo evidence suggesting that OST repressed EMT with preserved E-cadherin and reduced Vimentin expression in obstructed kidney. UUO injury-induced upregulation of EMT-related transcription factors, Snail family transcriptional repressor-1(Snail 1) and Twist family basic helix-loop-helix (BHLH) transcription factor (Twist) as well as elevated G2/M arrest of tubular epithelial cell, were rescued by OST treatment. Further, OST treatment reversed aberrant expression of TGFβ1-Smad signaling pathway, increased level of proinflammatory cytokines and NF-kappaB (NF-κB) activation in kidneys with obstructive nephropathy. Taken together, these findings suggest that OST hinder renal fibrosis in UUO mouse mainly through inhibition of fibroblast activation and EMT.
Highlights
Renal fibrosis caused by deposition and accumulation of extracellular matrix (ECM) components is the common final pathway of chronic kidney disease
The aim of this study was to assess the effect of OST on renal fibrosis in the mouse model of renal interstitial fibrosis induced by unilateral ureteral obstruction (UUO) and to examine if it could work through inhibiting renal fibroblast proliferation and epithelial to mesenchymal transition (EMT) program
OST Suppresses Activation and Proliferation of Renal Fibroblasts in vitro After 24 h stimulation with TGF-β1, expression of α-smooth muscle actin (α-SMA), FN (Fibronectin) and Col I were significantly increased in cultured fibroblasts (NRK-49F), whereas this effect was inhibited by administration of OST in a dose-dependent manner (Figures 1A,B)
Summary
Renal fibrosis caused by deposition and accumulation of extracellular matrix (ECM) components is the common final pathway of chronic kidney disease. There are no generally effective treatments for preventing the progression of renal fibrosis (Nogueira et al, 2017). The pharmacological mechanism of its action is still under investigation, but several potentially therapeutic effects have been demonstrated. It has been found to reduce tumor progression (Lin et al, 2014; Feng et al, 2017), have antibiotic properties (Wang et al, 2009), reduce allergic reactions (Chiang et al, 2017) and ameliorate osteoporosis (Zhang et al, 2017). Previous studies have indicated that OST may reduce fibrosis in the lung, liver and heart (Chen et al, 2011; Liu et al, 2015; Hao and Liu, 2016), but in renal tissue it is less studied. The present investigation was to focus on the effect of OST on renal tissue
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