title: YAP-mediated mechanotransduction determines the podocyte's response to damage.
abstract: 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 targetCTGFwas 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.
authors.affiliation: 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.
authors.forename: Markus M
authors.identifier: http://orcid.org/0000-0002-9252-1342
authors.initials: MM
authors.lastname: Rinschen
authors.affiliation: 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.
authors.forename: Florian
authors.initials: F
authors.lastname: Grahammer
authors.affiliation: Department of Internal Medicine II, University of Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Ann-Kathrin
authors.identifier: http://orcid.org/0000-0003-3046-9734
authors.initials: AK
authors.lastname: Hoppe
authors.affiliation: 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.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Kohli
authors.affiliation: Department of Internal Medicine II, University of Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Henning
authors.identifier: http://orcid.org/0000-0002-2624-2740
authors.initials: H
authors.lastname: Hagmann
authors.affiliation: 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.
authors.forename: Oliver
authors.initials: O
authors.lastname: Kretz
authors.affiliation: Department of Internal Medicine II, University of Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Bertsch
authors.affiliation: 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.
authors.forename: Martin
authors.identifier: http://orcid.org/0000-0001-8698-5389
authors.initials: M
authors.lastname: Höhne
authors.affiliation: Institute of Pathology, University of Cologne, Cologne, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Göbel
authors.affiliation: Department of Internal Medicine II, University of Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Malte P
authors.initials: MP
authors.lastname: Bartram
authors.affiliation: Department of Internal Medicine II, University of Cologne, Cologne, Germany.
authors.forename: Rajesh Kumar
authors.initials: RK
authors.lastname: Gandhirajan
authors.affiliation: 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.
authors.forename: Marcus
authors.initials: M
authors.lastname: Krüger
authors.affiliation: Department of Internal Medicine II, University of Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Paul-Thomas
authors.initials: PT
authors.lastname: Brinkkoetter
authors.affiliation: 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.|BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Freiburg, Germany.|Center for Biological Systems Analysis (ZBSA), Albert-Ludwigs-University Freiburg, Freiburg, Germany.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Huber
authors.affiliation: Department of Internal Medicine II, University of Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Kann
authors.affiliation: Cologne Cluster of Excellence in Cellular Stress Responses in Aging-associated Diseases, University of Cologne, Cologne, Germany.|Skin Homeostasis and Ageing, Paul Gerson Unna Research Group, Max Planck Institute for Biology of Ageing, Cologne, Germany.
authors.forename: Sara A
authors.identifier: http://orcid.org/0000-0001-6383-6292
authors.initials: SA
authors.lastname: Wickström
authors.affiliation: Department of Internal Medicine II, University of Cologne, Cologne, Germany. thomas.benzing@uk-koeln.de bernhard.schermer@uk-koeln.de.|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.
authors.forename: Thomas
authors.identifier: http://orcid.org/0000-0003-0512-1066
authors.initials: T
authors.lastname: Benzing
authors.affiliation: Department of Internal Medicine II, University of Cologne, Cologne, Germany. thomas.benzing@uk-koeln.de bernhard.schermer@uk-koeln.de.|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.
authors.forename: Bernhard
authors.identifier: http://orcid.org/0000-0002-5194-9000
authors.initials: B
authors.lastname: Schermer
mesh_terms: D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism; D008297:Male; D040542:Mechanotransduction, Cellular; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D050199:Podocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011507:Proteinuria / Q000235:genetics / Q000378:metabolism; D040901:Proteomics; D011692:Puromycin Aminonucleoside / Q000494:pharmacology; D051381:Rats; D013314:Stress, Mechanical; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D011692:Puromycin Aminonucleoside; D000217:Acyltransferases; C108675:TAFAZZIN protein, human