Piezo1 Channel as a Mechanosensor Driving Podocyte Hypertrophy in Obesity-Related Glomerulopathy

Background: The Piezo1 ion channel, a member of the mechanosensitive Piezo family, mediates cation influx—particularly Ca2+—in response to mechanical stimuli, regulating cell shape, motility, and function. Obesity-related glomerulopathy (ORG), characterized by glomerular hyperfiltration and podocyte hypertrophy, lacks a clearly defined molecular mechanism driving podocyte enlargement. Methods: We hypothesized that Piezo1 serves as a mechanosensor in podocytes and its overactivation contributes to podocyte hypertrophy and glomerular injury in obesity. Results: We confirmed robust expression of Piezo1—but not Piezo2—in murine podocytes both in vivo and in vitro. Using a podocyte-specific Piezo1 knockout mouse model (Piezo1fl/fl/Podocre), we found that despite similiar weight gain, Piezo1fl/fl/Podocre mice were protected from high-fat diet (HFD)-induced albuminuria compared to wild type (WT/WT) mice. Confocal microscopy showed increased Piezo1 expression in podocytes of HFD-fed WT/WT mice, which was absent in Piezo1fl/fl/Podocre mice. PAS staining and immunohistochemical staining of GLEPP1 revealed glomerulomegaly and podocyte hypertrophy in HFD-fed WT/WT mice but not in Piezo1fl/fl/Podocre mice. In vitro, the Piezo1 agonist Yoda1 induced dose-dependent podocyte hypertrophy. Using the Flexcell FX-6000 tension system, we found that mechanical stretching mimicking the increased mechanical stress on podocytes during obesity by 5% circumferential radius elongation of culture plates triggered remarkable podocyte hypertrophy, which was totally blocked by the 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, which was substantially reduced by the inclusion of GsMTx4 in pipette solution. Conclusion: Collectively, our data identify Piezo1 as a key mechanosensor in podocytes. Its overactivation in response to increased mechanical stress contributes to podocyte hypertrophy and glomerular injury in ORG, highlighting Piezo1 as a potential therapeutic target in ORG. Funding: NIDDK Support