Targeting Mechanosensitive Piezo1 Alleviated Renal Fibrosis Through p38MAPK-YAP Pathway.

Yuanyuan Fu,Jie Zhang,Pengzhi Wan,Kaiyue Wang,Yu Zou,Xiaoyue Zhai,Xue Li,Liu Cao,Hui Peng,Jia Xing,Qizhuo Zhu

doi:10.3389/fcell.2021.741060

Yuanyuan Fu, Jie Zhang + Show 9 more

Open Access

https://doi.org/10.3389/fcell.2021.741060

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Abstract

Renal fibrosis is the most common pathological manifestation of a wide variety of chronic kidney disease. Increased extracellular matrix (ECM) secretion and enhanced microenvironment stiffening aggravate the progression of renal fibrosis. However, the related mechanisms remain unclear. Here, we evaluated the mechanism by which ECM stiffness aggravates renal fibrosis. In the present study, renal mesangial cells (MCs) were cultured on polyacrylamide hydrogels with different stiffness accurately detected by atomic force microscope (AFM), simulating the in vivo growth microenvironment of MCs in normal kidney and renal fibrosis. A series of in vitro knockdown and activation experiments were performed to establish the signaling pathway responsible for mechanics-induced MCs activation. In addition, an animal model of renal fibrosis was established in mice induced by unilateral ureteral obstruction (UUO). Lentiviral particles containing short hairpin RNA (sh RNA) targeting Piezo1 were used to explore the effect of Piezo1 knockdown on matrix stiffness-induced MCs activation and UUO-induced renal fibrosis. An in vitro experiment demonstrated that elevated ECM stiffness triggered the activation of Piezo1, which increased YAP nuclear translocation through the p38MAPK, and consequently led to increased ECM secretion. Furthermore, these consequences have been verified in the animal model of renal fibrosis induced by UUO and Piezo1 knockdown could alleviate UUO-induced fibrosis and improve renal function in vivo. Collectively, our results for the first time demonstrate enhanced matrix stiffness aggravates the progression of renal fibrosis through the Piezo1-p38MAPK-YAP pathway. Targeting mechanosensitive Piezo1 might be a potential therapeutic strategy for delaying the progression of renal fibrosis.

Highlights

Chronic kidney disease (CKD) has become a serious public health problem endangering human health, which affects ∼10% of global population (Qiu et al, 2018)
These results demonstrate that extracellular matrix (ECM) stiffness activates Yes-associated protein (YAP) to promote mesangial cells (MCs) activation
We investigated the mechanism of renal fibrosis from the perspective of mechanical force

Summary

Introduction

Chronic kidney disease (CKD) has become a serious public health problem endangering human health, which affects ∼10% of global population (Qiu et al, 2018). Renal fibrosis is the most common pathological manifestation of a wide variety of CKD, which characterized by excessive deposition of extracellular matrix (ECM) including collagen fibers and fibronectin (Imamura et al, 2018). Abnormal mechanotransduction is correlated with the progression and severity of diseases including fibrosis (Li et al, 2019), cancer (Lee et al, 2019), and cardiovascular defects (Yamashiro et al, 2020). Increased ECM stiffness through collagen deposition or crosslinking accelerates ECM secretion and subsequently aggravates the progression of renal fibrosis, which forms a vicious positive feedback loop (Chen et al, 2014). Targeting the mechanotransduction signaling pathway induced by enhanced ECM stiffness may provide a therapeutic strategy for renal fibrosis. The effect of extracellular matrix mechanical microenvironment on MCs is not clear

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