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

Glomerular disease due to podocyte malfunction is a major factor in the pathogenesis of chronic kidney disease. Identification of podocyte-specific signaling pathways is therefore a prerequisite to characterizing relevant disease pathways and developing novel treatment approaches. Here, we employed loss of function studies for () as a central podocyte gene to generate a cell type-specific disease model. Loss of in fly nephrocytes caused protein uptake and slit diaphragm defects. Transcriptomic and proteomic analysis of human knockout podocytes demonstrated impaired mechanotransduction via the YAP/TAZ signaling pathway. Further analysis of specific inhibition of the YAP/TAZ-TEAD transcription factor complex by led to the identification of as an and YAP/TAZ-dependently expressed podocyte RhoGAP. Knockdown of caused increased RhoA activation, defective lamellipodia formation, and increased maturation of integrin adhesion complexes, explaining similar phenotypes caused by loss of and expression in podocytes. Detection of increased levels of ARHGAP29 in early disease stages of human glomerular disease implies a novel negative feedback loop for mechanotransductive RhoA-YAP/TAZ signaling in podocyte physiology and disease.