YAP‐mediated mechanotransduction determines the podocyte's response to injury

Podocytes are terminally differentiated cells at the kidney filtration barrier and exposed to considerable mechanical strain. Podocyte injury causes morphological alterations as a result of cytoskeletal reorganizations. This becomes clinically apparent as proteinuria owing to leakage of the renal filter. The transcriptional co‐activators YAP/TAZ are tightly controlled through Hippo signaling and responsive to mechanical cues. Here, we show that YAP is upregulated upon podocyte injury in vivo to induce YAP‐dependent target genes. This activation preceded the development of proteinuria. In contrast, similar perturbations of podocytes in cell culture revealed decreased YAP/TAZ activity when cells were grown on stiff surfaces. Notably, culture on soft matrix or inhibition of stress fiber formation both allowed recapitulation of the damage‐induced YAP upregulation observed in vivo indicating a mechanotransduction‐dependent mechanism of YAP hyper‐activity. Yap overexpression enhanced the proteome‐wide expression of proteins related to extracellular matrix generation. Interestingly, increased expression of the bona fide YAP target CTGF was confirmed in renal biopsies from patients with glomerular disease. Consistently, genetic activation of YAP could induce mild proteinuria while pharmacological inhibition of YAP/TEAD activity ameliorated glomerular disease and damage‐induced mechanosignaling in vivo . Therefore, our findings suggest that perturbation of the mechanosensitive Hippo signaling pathway could be used as a therapeutic principle in podocyte disease. Support or Funding Information DFG