The extracellular matrix Piezo1 feedback loop drives renal fibrosis through compartment-specific mechanotransduction

Renal fibrosis is the final common pathological outcome of chronic kidney disease and is characterized not only by excessive extracellular matrix (ECM) deposition but also by profound and persistent alterations in tissue mechanics. Among emerging mechanosensors, the mechanosensitive ion channel Piezo1 has gained attention as a direct transducer of mechanical forces into intracellular calcium signaling. This review reframes renal fibrosis as a self-reinforcing mechanobiological process driven by an ECM–Piezo1 feedback loop, rather than a purely biochemical cascade. In the kidney, pathological mechanical cues including matrix stiffening, tissue stretch, and blood pressure activate Piezo1 in tubular epithelial cells, mesangial cells, fibroblasts, and immune cells. Piezo1-mediated Ca²⁺ influx interfaces with integrin-based adhesion complexes, cytoskeletal tension systems, and canonical profibrotic signaling pathways, thereby amplifying extracellular matrix synthesis, epithelial–mesenchymal transition, inflammatory activation, and metabolic dysregulation. These interactions establish a self-reinforcing mechanobiological loop in which ECM stiffening enhances Piezo1 activation, further promoting matrix remodeling and tissue rigidity. This review summarizes current knowledge of ECM composition and mechanical remodeling in the kidney, delineates the molecular mechanisms underlying Piezo1-dependent mechanotransduction, and discusses the compartment-specific roles of the ECM–Piezo1 axis in glomerular, tubular, and immune cell populations. We further highlight emerging therapeutic strategies targeting this axis, including pharmacologic modulation of Piezo1 activity, gene- and cell-based approaches, and biomaterial-guided mechanical reprogramming. Here, we provide a kidney-centered, compartment-specific synthesis of ECM–Piezo1 mechanotransduction, highlighting how progressive matrix stiffening perpetuates compartment-specific pathological signaling and revealing precision intervention points beyond global Piezo1 blockade.