Key Role of Piezo1 Channel in Podocyte Hypertrophy during Obesity

The Piezo1 ion channel, a member of the mechanosensitive Piezo family, responds to various mechanical forces by allowing cation influx, particularly Ca 2+ , into cells, leading to changes in cell shape, motility, and function. Obesity-related glomerulopathy (ORG) is a chronic glomerular disease characterized by glomerular hyperfiltration and podocyte hypertrophy. However, the molecular mechanisms underlying podocyte hypertrophic change in obesity remains unclear. Given that glomerular hyperfiltration is associated with increased mechanical forces on podocytes, we hypothesize that the Piezo1 channel may act as a mechanosensor in podocytes, with overactivation contributing to podocyte hypertrophy and glomerular injury in obesity. We confirmed that Piezo1 but not Piezo2 was highly expressed in murine podocytes in vivo and in vitro. To test our hypothesis, we generated a podocyte-specific Piezo1 gene knockout (Piezo1 fl/fl /Podo cre ) mouse strain. After treatment with normal diet (ND) or high-fat diet (HFD) for 12 weeks, Piezo1 fl/fl /Podo cre mice were protected from HFD-induced albuminuria compared to wild type (WT/WT) mice, without differences in weight gain. Confocal microscopy revealed elevated podocyte Piezo1 expression in HFD-fed WT/WT mice, which was absent in Piezo1 fl/fl /Podo cre mice. PAS staining and immunohistochemical staining of GLEPP1 (podocyte apical cell membrane marker) showed glomerulomegaly and podocyte hypertrophy in HFD-fed WT/WT mice, but not in Piezo1 fl/fl /Podo cre mice on HFD. In vitro, we demonstrated that Piezo1 channel agonist, Yoda1, significantly increased podocyte size in a dose-dependent manner. Using Flexcell FX-6000 tension system, we found that mechanical stretching mimicking increased mechanical stress on podocytes during obesity by 5% circumferential radius elongation of culture plates triggered remarkable podocyte hypertrophy, which was totally blocked by Piezo1 channel inhibitor, GsMTx4. By cell-attached patch clamp recording, a voltage-dependent single-channel activity of Piezo1 was recorded in the presence of Yoda1 in pipette solution with a conductance of 28.5 pS. Moreover, application of negative pressure (-40 mmHg) in recording pipette using a high-speed pressure clamp system, HSPC-1 remarkedly increased single channel opening on podocyte membrane with holding potential at -50 mV (the membrane potential of podocytes), which was substantially reduced by the inclusion of GsMTx4 in pipette solution. Fura-2 Ca 2+ imaging demonstrated that Yoda1 induced Ca 2+ influx in WT/WT podocytes but not in podocytes lacking Piezo1 gene. Taken together, our findings suggest that Piezo1 channel plays a vital role in mechanosensing in podocytes. Overactivation of Piezo1 channel in response to increased mechanical forces associated with glomerular hyperfiltration may trigger podocyte hypertrophy and thereby contribute to glomerular injury in ORG. This study is supported by NIH grants DK054927 and DK120491. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.