Abstract
Kidney fibrosis is the final common pathway of progressive kidney diseases, the underlying mechanisms of which are not fully understood. The purpose of the current study is to investigate a role of Piezo1, a mechanosensitive nonselective cation channel, in kidney fibrosis. In human fibrotic kidneys, Piezo1 protein expression was markedly upregulated. The abundance of Piezo1 protein in kidneys of mice with unilateral ureter obstruction (UUO) or with folic acid treatment was significantly increased. Inhibition of Piezo1 with nonspecific inhibitor GsMTx4 markedly ameliorated UUO- or folic acid–induced kidney fibrosis. Mechanical stretch, compression, or stiffness induced Piezo1 activation and profibrotic responses in human HK2 cells and primary cultured mouse proximal tubular cells (mPTCs), which were greatly prevented by inhibition or silence of Piezo1. TGF-β1 induced increased Piezo1 expression and profibrotic phenotypic alterations in HK2 cells and mPTCs, which were again markedly prevented by inhibition of Piezo1. Activation of Piezo1 by Yoda1, a Piezo1 agonist, caused calcium influx and profibrotic responses in HK2 cells and induced calcium-dependent protease calpain2 activation, followed by adhesion complex protein talin1 cleavage and upregulation of integrin β1. Also, Yoda1 promoted the link between ECM and integrin β1. In conclusion, Piezo1 is involved in the progression of kidney fibrosis and profibrotic alterations in renal proximal tubular cells, likely through activating calcium/calpain2/integrin β1 pathway.
Highlights
Kidney fibrosis is the final common outcome of chronic kidney diseases, leading to the end stage of kidney diseases [1]
Tubular Piezo1 protein abundance was markedly increased, while inhibition of Piezo1 by a blocker, GsMTx4, attenuated tubulointerstitial fibrosis induced by ureter obstruction (UUO) or folic acid
We demonstrated that Piezo1 stimulation by mechanical stretch, compression, stiffness, or an agonist, Yoda1, induced profibrotic alterations in HK2 cells, while transforming growth factor-β1 (TGF-β1)–induced profibrotic response was partially prevented by inhibition or silence of Piezo1
Summary
Kidney fibrosis is the final common outcome of chronic kidney diseases, leading to the end stage of kidney diseases [1]. Renal fibrogenesis is a dynamic and converging process, in which several types of cells, mainly tubular epithelial cells and interstitial fibroblasts, play important roles in tubulointerstitial fibrosis after an insult to the renal parenchyma [2]. Tubular epithelium is able to detect tiny changes in matrix stiffness and, in response, to adjust expression of genes and proteins important in cell proliferation, differentiation, and apoptosis [3, 4]. After severe or repeated injuries, tubular epithelial cells may exhibit a series of characteristic alterations and acquire mesenchymal traits, leading to proinflammatory and profibrotic phenotypic changes [5, 6]. It is possible that EMT may represent tubular injuries, epithelial plasticity, or profibrotic phenotypic changes. TGF-β1 may directly induce tubular injuries and the production of ECM in the kidney through TGF-β1/ Smad signaling, leading to renal fibrosis [9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
