Emerging Therapeutic Strategies for Attenuating Tubular EMT and Kidney Fibrosis by Targeting Wnt/β-Catenin Signaling.

Lichao Hu,Weichun He,Mengyuan Ding

doi:10.3389/fphar.2021.830340

Abstract

Epithelial-mesenchymal transition (EMT) is defined as a process in which differentiated epithelial cells undergo phenotypic transformation into myofibroblasts capable of producing extracellular matrix, and is generally regarded as an integral part of fibrogenesis after tissue injury. Although there is evidence that the complete EMT of tubular epithelial cells (TECs) is not a major contributor to interstitial myofibroblasts in kidney fibrosis, the partial EMT, a status that damaged TECs remain inside tubules, and co-express both epithelial and mesenchymal markers, has been demonstrated to be a crucial stage for intensifying fibrogenesis in the interstitium. The process of tubular EMT is governed by multiple intracellular pathways, among which Wnt/β-catenin signaling is considered to be essential mainly because it controls the transcriptome associated with EMT, making it a potential therapeutic target against kidney fibrosis. A growing body of data suggest that reducing the hyperactivity of Wnt/β-catenin by natural compounds, specific inhibitors, or manipulation of genes expression attenuates tubular EMT, and interstitial fibrogenesis in the TECs cultured under profibrotic environments and in animal models of kidney fibrosis. These emerging therapeutic strategies in basic researches may provide beneficial ideas for clinical prevention and treatment of chronic kidney disease.

Highlights

A pathological process characterized by excessive deposition of extracellular matrix (ECM) in the interstitium accompanied by destruction of normal kidney architecture, is a hallmark and inevitable end point of all kinds of progressive chronic kidney disease (CKD)
We have reported that FHL2 was upregulated in the fibrotic kidneys in CKD patients and in ureteral obstruction (UUO) mice and in the TGFβ1-treated tubular epithelial cells (TECs) (Cai et al, 2018; Duan et al, 2020)
TECs undergoing conventional epithelial-mesenchymal transition (EMT) are no longer recognized as a major constituent of interstitial myofibroblasts, the partial EMT has been demonstrated to exert the crucial functions in the fibrogenesis during kidney fibrosis progression

Summary

Introduction

A pathological process characterized by excessive deposition of extracellular matrix (ECM) in the interstitium accompanied by destruction of normal kidney architecture, is a hallmark and inevitable end point of all kinds of progressive chronic kidney disease (CKD). In TECs, Wnt/β-catenin signaling takes effects by inducing its target genes, some of which play the substantial roles in regulating tubular EMT process in the setting of CKD, such as fibroblastspecific protein 1 (FSP-1), fibronectin, matrix metalloproteinase 7 (MMP7), Snail, and Twist (Boutet et al, 2006; He et al, 2009; He et al, 2012; Tan et al, 2014; Ning et al, 2018).

Results

Conclusion