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Sci Signal. 2017 Apr 11;10(474). pii: eaaf8165. doi: 10.1126/scisignal.aaf8165.

YAP-mediated mechanotransduction determines the podocyte's response to damage.

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Department of Internal Medicine II, University of Cologne, Cologne, Germany.
Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
Cologne Cluster of Excellence in Cellular Stress Responses in Aging-associated Diseases, University of Cologne, Cologne, Germany.
Systems Biology of Ageing Cologne, University of Cologne, Cologne, Germany.
Department of Medicine IV, Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany.
III. Medical Clinic and Polyclinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Department of Neuroanatomy, Institute of Anatomy, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Institute of Pathology, University of Cologne, Cologne, Germany.
BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
Center for Biological Systems Analysis (ZBSA), Albert-Ludwigs-University Freiburg, Freiburg, Germany.
Skin Homeostasis and Ageing, Paul Gerson Unna Research Group, Max Planck Institute for Biology of Ageing, Cologne, Germany.
Department of Internal Medicine II, University of Cologne, Cologne, Germany.


Podocytes are terminally differentiated cells of the kidney filtration barrier. They are subjected to physiological filtration pressure and considerable mechanical strain, which can be further increased in various kidney diseases. When injury causes cytoskeletal reorganization and morphological alterations of these cells, the filtration barrier may become compromised and allow proteins to leak into the urine (a condition called proteinuria). Using time-resolved proteomics, we showed that podocyte injury stimulated the activity of the transcriptional coactivator YAP and the expression of YAP target genes in a rat model of glomerular disease before the development of proteinuria. Although the activities of YAP and its ortholog TAZ are activated by mechanical stress in most cell types, injury reduced YAP and TAZ activity in cultured human and mouse podocyte cell lines grown on stiff substrates. Culturing these cells on soft matrix or inhibiting stress fiber formation recapitulated the damage-induced YAP up-regulation observed in vivo, indicating a mechanotransduction-dependent mechanism of YAP activation in podocytes. YAP overexpression in cultured podocytes increased the abundance of extracellular matrix-related proteins that can contribute to fibrosis. YAP activity was increased in mouse models of diabetic nephropathy, and the YAP target CTGF was highly expressed in renal biopsies from glomerular disease patients. Although overexpression of human YAP in mice induced mild proteinuria, pharmacological inhibition of the interaction between YAP and its partner TEAD in rats ameliorated glomerular disease and reduced damage-induced mechanosignaling in the glomeruli. Thus, perturbation of YAP-dependent mechanosignaling is a potential therapeutic target for treating some glomerular diseases.

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