PIEZO1-Mediated Calcium Signaling and Podocyte Injury in Diabetic Kidney Disease

Key Points Diabetic kidney disease progression was associated with increased Piezo1 expression in podocytes. Specific Piezo1 deletion alleviated podocyte injury in diabetic models. Piezo1 contributes to podocyte injury through nuclear factor of activated T cell cytoplasmic 1–transient receptor potential cation channel 6 signaling. Background Diabetic kidney disease (DKD) is characterized by progressive injury to glomerular podocytes due to sustained mechanical stress within the glomerulus. Piezo proteins, acting as cellular mechanosensors, play a pivotal role in mechanotransduction by sensing mechanical forces and regulating intracellular ion flux. This study investigates the role of Piezo1 in the progression of DKD and its mechanistic involvement in podocyte injury. Methods Podocyte-specific Piezo1 knockout mice were generated using the streptozotocin plus high-fat diet model of DKD. In vitro studies included the use of Piezo1 inhibitors to assess calcium influx, podocyte cytoskeletal rearrangement, and apoptosis under stiff matrix conditions. In addition, NF of activated T-cell cytoplasmic 1 (NFATc1) and transient receptor potential cation channel 6 (TRPC6) signaling pathways were explored to establish their role in Piezo1-mediated podocyte injury. Adeno-associated virus TRPC6 was used to overexpress TRPC6 in podocyte-specific Piezo1 knockout mice to assess the in vivo interaction between Piezo1 and TRPC6. Results Podocyte-specific deletion of Piezo1 significantly ameliorated the progression of DKD in diabetic mice. Inhibition of Piezo1 reduced calcium influx, cytoskeletal rearrangement, and podocyte apoptosis in vitro . Mechanistically, Piezo1 activation triggered a signaling loop involving NFATc1 and TRPC6, leading to increased calcium influx, perpetuating podocyte injury. TRPC6 overexpression in vivo counteracted the protective effects of Piezo1 deletion, confirming the critical role of the Piezo1/NFATc1/TRPC6 axis in DKD progression. Conclusions Piezo1 plays a key mechanosensory role in podocyte injury during DKD progression by mediating calcium influx and activating the NFATc1/TRPC6 signaling pathway.