Mechanotransductive receptor Piezo1 as a promising target in the treatment of fibrosis diseases

Abstract

Fibrosis could happen in every organ, leading to organic malfunction and even organ failure, which poses a serious threat to global health. Early treatment of fibrosis has been reported to be the turning point, therefore, exploring potential correlates in the pathogenesis of fibrosis and how to reverse fibrosis has become a pressing issue. As a mechanism-sensitive cationic calcium channel, Piezo1 turns on in response to changes in the lipid bilayer of the plasma membrane. Piezo1 exerts multiple biological roles, including inhibition of inflammation, cytoskeletal stabilization, epithelial-mesenchymal transition, stromal stiffness, and immune cell mechanotransduction, interestingly enough. These processes are closely associated with the development of fibrotic diseases. Recent studies have shown that deletion or knockdown of Piezo1 attenuates the onset of fibrosis. Therefore, in this paper we comprehensively describe the biology of this gene, focusing on its potential relevance in pulmonary fibrosis, renal fibrosis, pancreatic fibrosis, and cardiac fibrosis diseases, except for the role of drugs (agonists), increased intracellular calcium and mechanical stress using this gene in alleviating fibrosis.

Keywords: Ca2+; Piezo1; Piezo2; fibrosis; therapeutic target.

FIGURE 1

Schematic diagram of the mechanism by which mechanical stimulation of ATII cells activates Piezo1 channels to trigger related pathways. After activation of Piezo1 by mechanical signals, calcium ions inwardly flowed into the cells, and Piezo1 regulated TGF-β1 through the Ca2+/HIF-1α signaling pathway, leading to upregulation of TGF-β1. The upregulation of TGF-β1 could on the one hand activate the EMT through the MAPK and smad-dependent signaling pathways to promote lung fibrosis, on the other hand, and might inhibit C/EBPβ by the Smad3 pathway, which could inhibit the effect of C/EBPβ on the promoter of Piezo1, and result in the upregulation of Piezo1’s expression as well.

FIGURE 2

Schematic diagram of the Piezo1-related pathway mechanisms in renal fibrosis. Mechanical signaling or Yoda1 activates cellular Piezo1 channels after acting on HK2 cells and mptc. TGF-β1 induces upregulation of fibronectin and α-SMA, resulting in increased ECM synthesis. Activation of calpain2, which signals downstream of Piezo1, induces talin1 clearance and upper-regulation of integrin β1 protein, and increased ECM stiffness. A large number of calcium ions inward flow may activate P38-MAPK molecules, P38-MAPK then activates YAP, and YAP induces ECM deposition, which promotes the process of renal fibrosis.

FIGURE 3

Schematic diagram of Piezo1 channels in pancreatic alveolar cells and PSCs cells associated with pancreatic fibrosis. (1) After prolonged high pressure is applied to the alveolar cells, the opening of Piezo1 channels activates PLA2 channels, which in turn induces the opening of TRPV4 channels, which ultimately allows for the sustained inward flow of calcium ions, causing pancreatitis with concomitant pancreatic fibrosis. (2) After the continuous action of high pressure on PSCs, PSCs were activated to secrete cellular inflammatory factors such as IL-6, IL-1β, TNF-α, etc., which could accelerate the damage of alveolar cells and lead to pancreatitis complicated by pancreatic fibrosis. Meanwhile, PSCs can activate macrophages to recruit inflammatory monocytes, and secrete TNF-α and TGF-β, which also accelerate the development of pancreatic fibrosis by promoting inflammation. (3) PSCs can secrete ECM proteins leading to pancreatic fibrosis, and after pancreatitis occurs, pancreatic alveolar cells can activate PSCs by secreting cellular inflammatory factors, accelerating the development of pancreatic fibrosis.

FIGURE 4

Schematic diagram of the mechanism by which Piezo1 channels in cardiac fibroblasts are associated with cardiac fibrosis. (1) Activation of Piezo1 triggers the activation of calcium ions and promotes fibroblasts into myofibroblasts, which are capable of secreting cytokines, including IL-6, etc. Increased calcium ions activate the downstream signaling pathway p38-MAPK, thereby increasing the level of IL-6. (2) After mechanical stimulation of Piezo1 channel opening, Nppb responded to mechanical stretching by expressing BNP, which inhibited TGF-β1 and also further inhibited the promotion of cardiac fibrosis by TGF-β1.