Piezo1, F-Actin Remodeling, and Podocyte Survival and Regeneration

Key Points Piezo1 regulates perinuclear actin remodeling, and its loss induces nuclear envelope defects and accumulation of DNA damage. Piezo1 loss in podocytes leads to mitotic catastrophe. Podocyte-specific and podocyte progenitor–specific knockout of Piezo1 in mice result in severe albuminuria after adriamycin nephropathy. Background Podocytes and podocyte progenitors are interdependent components of the kidney's glomerular structure, with podocytes forming the glomerular filtration barrier and progenitors being key players in podocyte regeneration during pathophysiologic processes. Both cell types are subjected to constant mechanical forces, whose alterations can initiate podocytopathy and worsen glomerular injury. Despite this, the specific mechanosensors and mechanotransduction pathways involved in their response to mechanical cues remain only partially explored. Methods We used transcriptomics, immunofluorescence, and silencing experiments on human primary podocyte progenitor cell cultures to demonstrate the expression and function of Piezo1 channels. We generated inducible podocyte-specific and podocyte progenitor–specific Piezo1 knockout (KO) mice to evaluate the effects of Piezo1 loss in the context of adriamycin nephropathy and over 10 months of aging. Results Silencing of Piezo1 in progenitors triggered F-actin remodeling, which induced cell shape modification and nuclear envelope defects with accumulation of DNA damage that led to mitotic catastrophe in differentiated podocytes. Podocyte-specific KO of Piezo1 induced higher susceptibility to podocyte injury in adriamycin nephropathy and led to accumulation of DNA damage and mild albuminuria starting from adult age. Podocyte progenitor–specific KO of Piezo1 in mouse resulted in severe albuminuria during adriamycin nephropathy, leading to the generation of defective podocytes. Conclusions These results demonstrated that Piezo1, thanks to its role in F-actin cytoskeleton maintenance, is essential for the survival of podocytes exposed to mechanical stress conditions and for their correct regeneration.