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 forEPB41L5(Yurt) as a central podocyte gene to generate a cell type-specific disease model. Loss ofYurtin fly nephrocytes caused protein uptake and slit diaphragm defects. Transcriptomic and proteomic analysis of humanEPB41L5knockout podocytes demonstrated impaired mechanotransduction via the YAP/TAZ signaling pathway. Further analysis of specific inhibition of the YAP/TAZ-TEAD transcription factor complex byTEADiled to the identification ofARGHAP29as anEPB41L5and YAP/TAZ-dependently expressed podocyte RhoGAP. Knockdown ofARHGAP29caused increased RhoA activation, defective lamellipodia formation, and increased maturation of integrin adhesion complexes, explaining similar phenotypes caused by loss ofEPB41L5andTEADiexpression 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.