Dataset Information

Response of podocytes to PAN - YAP-mediated mechanotransduction determines the podocyte's response to damage

ABSTRACT: Podocytes are terminally differentiated cells at the kidney filtration barrier and exposed to considerable mechanical strain. Podocyte injury causes morphological changes as a result of cytoskeletal reorganizations and failure of the filtration barrier. 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 to activate YAP-dependent target genes. This activation preceded the development of proteinuria. In contrast, similar perturbations of cells in culture did not reveal increased YAP activity but showed a downregulation of YAP/TAZ activity when cells were grown on stiff surface. However, culture of cells on soft matrix or inhibition of stress fiber formation allowed recapitulation of the damage-induced YAP upregulation indicating a mechanotransduction-dependent mechanism of YAP over-activity. Interestingly, increased expression of YAP targets was confirmed in renal biopsies from patients with glomerular disease. Consistently, pharmacological inhibition of YAP/TEAD activity ameliorated glomerular disease in vivo. These data suggest that perturbation of the mechanosensitive hippo signaling pathway may be a therapeutic principle in podocyte disease.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Glomerular Visceral Epithelial Cell, Kidney

DISEASE(S): Nephrotic Syndrome

SUBMITTER: Markus Rinschen

LAB HEAD: Bernhard Schermer, Markus Rinschen

PROVIDER: PXD003872 | Pride | 2017-04-19

REPOSITORIES: Pride

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			Action	DRS
	20150527_RG_Benzing_Rinschen_150523_TQ_S01.raw	Raw
	20150527_RG_Benzing_Rinschen_150523_TQ_S02.raw	Raw
	20150527_RG_Benzing_Rinschen_150523_TQ_S07.raw	Raw
	20150527_RG_Benzing_Rinschen_150523_TQ_S08.raw	Raw
	20150527_RG_Benzing_Rinschen_150523_TQ_S09.raw	Raw

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

Rinschen Markus M MM Grahammer Florian F Hoppe Ann-Kathrin AK Kohli Priyanka P Hagmann Henning H Kretz Oliver O Bertsch Sabine S Höhne Martin M Göbel Heike H Bartram Malte P MP Gandhirajan Rajesh Kumar RK Krüger Marcus M Brinkkoetter Paul-Thomas PT Huber Tobias B TB Kann Martin M Wickström Sara A SA Benzing Thomas T Schermer Bernhard B

Science signaling 20170411 474

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 podocyt ...[more]

PMID: 28400537

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