Kidney Week

Abstract: FR-PO0758

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

Session Information

• Glomerular Diseases: Cell Homeostasis and Novel Injury Mechanisms
  November 07, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Li, Guangbi, Virginia Commonwealth University, Richmond, Virginia, United States

Guangbi Li, PhD

• Kidd, Jason M., Virginia Commonwealth University, Richmond, Virginia, United States

Jason M. Kidd, MD, FASN

• Zou, Yao, Virginia Commonwealth University, Richmond, Virginia, United States

Yao Zou

• Li, Ningjun, Virginia Commonwealth University, Richmond, Virginia, United States

Ningjun Li, MD

• Gehr, Todd W., Virginia Commonwealth University, Richmond, Virginia, United States

Todd W. Gehr, MD, FASN

• Li, Pin-lan, Virginia Commonwealth University, Richmond, Virginia, United States

Pin-lan Li, MD, PhD

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 (Piezo1^fl/fl/Podo^cre), we found that despite similiar weight gain, Piezo1^fl/fl/Podo^cre 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 Piezo1^fl/fl/Podo^cre mice. PAS staining and immunohistochemical staining of GLEPP1 revealed glomerulomegaly and podocyte hypertrophy in HFD-fed WT/WT mice but not in Piezo1^fl/fl/Podo^cre 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

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025esr51we0