Targeting Mechanosensitive Piezo1 Alleviated Renal Fibrosis Through p38MAPK-YAP Pathway

Frontiers in Cell and Developmental Biology

Liu Cao¹  Jia Xing²  Yu Zou²  Yuanyuan Fu²  Jie Zhang²  Kaiyue Wang²  Qizhuo Zhu²  Pengzhi Wan³  Hui Peng⁴  Xue Li⁴  Xiaoyue Zhai⁵ 

[1] Department of Basic Medical College, China Medical University, Shenyang, China;Department of Histology and Embryology, Basic Medical College, China Medical University, Shenyang, China;Department of Nephrology, First Affiliated Hospital of China Medical University, Shenyang, China;Department of Nephrology, Shengjing Hospital of China Medical University, Shenyang, China;Institute of Nephropathology, China Medical University, Shenyang, China;

关键词: renal fibrosis;    matrix stiffness;    extracellular matrix secreation;    Piezo1;    YAP;   

DOI  :  10.3389/fcell.2021.741060

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown