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A YAP/TAZ-ARHGAP29-RhoA Signaling Axis Regulates Podocyte Protrusions and Integrin Adhesions

Manuel Rogg1, Jasmin I Maier1, Martin Helmstädter2

  • 1Institute of Surgical Pathology, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.

Cells
|July 14, 2023
PubMed

Insights

Podocyte malfunction in glomerular disease impairs kidney function. Researchers identified EPB41L5 (Yurt) as crucial for mechanotransduction, revealing ARHGAP29 as a key player in kidney disease progression.

Area of Science:

  • Nephrology
  • Cell Biology
  • Molecular Biology

Background:

  • Glomerular diseases, often stemming from podocyte dysfunction, significantly contribute to chronic kidney disease pathogenesis.
  • Understanding podocyte-specific signaling is vital for elucidating disease mechanisms and developing targeted therapies.

Purpose of the Study:

  • To investigate the role of EPB41L5 (Yurt) in podocyte function and mechanotransduction.
  • To identify novel signaling pathways and molecular players involved in podocyte disease.

Main Methods:

  • Loss-of-function studies of EPB41L5 (Yurt) in Drosophila nephrocytes and human podocytes.
  • Transcriptomic and proteomic analyses of EPB41L5 knockout podocytes.
  • Inhibition of the YAP/TAZ-TEAD transcription factor complex.
  • Knockdown of ARHGAP29 and assessment of RhoA activation and cell morphology.

Main Results:

  • Loss of Yurt in nephrocytes led to protein uptake and slit diaphragm defects.
  • EPB41L5 deficiency in human podocytes impaired YAP/TAZ-mediated mechanotransduction.
  • ARHGAP29 was identified as an EPB41L5 and YAP/TAZ-dependent gene.
  • ARHGAP29 knockdown mimicked EPB41L5 loss-of-function phenotypes, including RhoA activation and altered cell adhesion.

Conclusions:

  • EPB41L5 is essential for podocyte mechanotransduction via the YAP/TAZ pathway.
  • ARHGAP29 acts as a downstream effector, mediating EPB41L5 and YAP/TAZ signaling in podocytes.
  • Elevated ARHGAP29 in early glomerular disease suggests a novel feedback loop in podocyte mechanotransduction.
Keywords:
ARHGAP29EPB41L5YAP/TAZYurtglomerular kidney diseasemechanotransductionpodocyte

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