Targeting Mechanosensitive Piezo1 Alleviated Renal Fibrosis Through p38MAPK-YAP Pathway

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.

Piezo1 Channel as a Potential Target for Hindering Cardiac Fibrotic Remodeling

“…As discussed for tumor cases and as already proposed for renal tumors [ 21 , 121 , 149 ], Piezo1 could also be, at least, a biomarker for discriminating the aggressiveness of cardiac fibrosis and, at most, a beneficial therapeutic target. Moreover, the possibility of restoring its physiological activity may interrupt the positive feedback in which its increased activity promotes ECM remodeling in a way in which its stiffness-induced stimulated activity is again enhanced.…”

Piezo2 expression and its alteration by mechanical forces in mouse mesangial cells and renin-producing cells

“…Mechanosensors in mesangial cells remained unidentified for a long time. Quite recently, Fu et al 38 reported that Piezo1 is involved in ECM gene expression in cultured mesangial cells under mechanical stress and in renal fibrosis in a mouse model. They used an unconventional method of culturing cells on hydrogel with different stiffness to evaluate the effects of mechanical stress.…”

A Review on the Design of Hydrogels With Different Stiffness and Their Effects on Tissue Repair

“…In the experiments of Wang et al (2020b) , they found that Piezo1 could perceive mechanical load, and Piezo1 could regulate the expression of type II and type IX collagens by changing the nuclear localization of YAP, thus affecting the osteogenic process. In addition, the expression of Piezo1 increased with the rise of gel stiffness in the external environment ( Sun et al, 2020 ; Fu et al, 2021 ). The related experiments carried out by Sun et al with human umbilical cord mesenchymal stem cells (hUC-MSCs) revealed the interaction among Piezo1, integrin and Ca 2+ .…”