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Front. Physiol. | doi: 10.3389/fphys.2018.01650

Osthole ameliorates renal fibrosis in mice by suppressing fibroblast activation and epithelial-mesenchymal transition

 Suping Zhang1, 2, Qian Huang1, 3,  Shan Jiang1, 2, Nan Xu1, 2, Qin Zhou1, 2, Xiaoyun Cao1, 2,  Michael Hultström4,  Jiong Tian1, 5* and  En Yin Lai1, 2
  • 1Zhejiang University, China
  • 2Zhejiang Hospital, China
  • 3Quanzhou Medical College, China
  • 4Uppsala University, Sweden
  • 5First Affiliated Hospital, College of Medicine, Zhejiang University, China

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.

Keywords: Osthole, fibroblast, Epithe lial-mesenchymal transition, Inflammation, renal fibrosis (RF)

Received: 11 Sep 2018; Accepted: 31 Oct 2018.

Edited by:

Susan Yung, University of Hong Kong, Hong Kong

Reviewed by:

Yin Xia, The Chinese University of Hong Kong, China
Bo Wang, Monash University, Australia  

Copyright: © 2018 Zhang, Huang, Jiang, Xu, Zhou, Cao, Hultström, Tian and Lai. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Jiong Tian, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China, jiongtian@zju.edu.cn