Rinschen, Markus M., Grahammer, Florian, Hoppe, Ann-Kathrin, Kohli, Priyanka ORCID: 0000-0002-0651-4008, Hagmann, Henning, Kretz, Oliver, Bertsch, Sabine, Hoehne, Martin, Goebel, Heike, Bartram, Malte P., Gandhirajan, Rajesh Kumar, Krueger, Marcus, Brinkkoetter, Paul-Thomas, Huber, Tobias B. ORCID: 0000-0001-7175-5062, Kann, Martin, Wickstroem, Sara A., Benzing, Thomas and Schermer, Bernhard ORCID: 0000-0002-5194-9000 (2017). YAP-mediated mechanotransduction determines the podocyte's response to damage. Sci. Signal., 10 (474). WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE. ISSN 1937-9145

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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 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Rinschen, Markus M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grahammer, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoppe, Ann-KathrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kohli, PriyankaUNSPECIFIEDorcid.org/0000-0002-0651-4008UNSPECIFIED
Hagmann, HenningUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kretz, OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bertsch, SabineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoehne, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goebel, HeikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bartram, Malte P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gandhirajan, Rajesh KumarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krueger, MarcusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brinkkoetter, Paul-ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huber, Tobias B.UNSPECIFIEDorcid.org/0000-0001-7175-5062UNSPECIFIED
Kann, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wickstroem, Sara A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Benzing, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schermer, BernhardUNSPECIFIEDorcid.org/0000-0002-5194-9000UNSPECIFIED
URN: urn:nbn:de:hbz:38-233998
DOI: 10.1126/scisignal.aaf8165
Journal or Publication Title: Sci. Signal.
Volume: 10
Number: 474
Date: 2017
Publisher: AMER ASSOC ADVANCEMENT SCIENCE
Place of Publication: WASHINGTON
ISSN: 1937-9145
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
FOOT PROCESS EFFACEMENT; TISSUE GROWTH-FACTOR; KIDNEY FILTRATION BARRIER; DIABETIC-NEPHROPATHY; HIPPO PATHWAY; TGF-BETA; PHOSPHOPROTEOMIC ANALYSIS; PROTEOMIC ANALYSIS; IMAGE-ANALYSIS; CELL BIOLOGYMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/23399

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