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

Rinschen, M. M., Grahammer, F., Hoppe, A. K., Kohli, P., Hagmann, H., Kretz, O., Bertsch, S., Hohne, M., Gobel, H., Bartram, M. P., Gandhirajan, R. K., Kruger, M., Brinkkoetter, P. T., Huber, T. B., Kann, M., Wickstrom, S. A., Benzing, T., & Schermer, B. (2017). YAP-mediated mechanotransduction determines the podocyte's response to damage. Sci Signal, 10(474). doi:10.1126/scisignal.aaf8165.

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アイテムのパーマリンク: https://hdl.handle.net/21.11116/0000-0001-5924-3 版のパーマリンク: https://hdl.handle.net/21.11116/0000-0001-5925-2
資料種別: 学術論文

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URL:
https://www.ncbi.nlm.nih.gov/pubmed/28400537 (全文テキスト（全般）)
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 作成者:
Rinschen, M. M.1, 著者
Grahammer, F.1, 著者
Hoppe, A. K.1, 著者
Kohli, P.1, 著者
Hagmann, H.1, 著者
Kretz, O.1, 著者
Bertsch, S.1, 著者
Hohne, M.1, 著者
Gobel, H.1, 著者
Bartram, M. P.1, 著者
Gandhirajan, R. K.1, 著者
Kruger, M.1, 著者
Brinkkoetter, P. T.1, 著者
Huber, T. B.1, 著者
Kann, M.1, 著者
Wickstrom, S. A.1, 著者
Benzing, T.1, 著者
Schermer, B.1, 著者
所属:
1Max Planck Institute for Biology of Ageing, Max Planck Society, Joseph-Stelzmann-Str. 9b, D-50931 Cologne, DE, ou_1942284              

内容説明

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キーワード: Adaptor Proteins, Signal Transducing/genetics/*metabolism Animals Cell Line Diabetic Nephropathies/genetics/metabolism Fluorescent Antibody Technique HEK293 Cells Humans Kidney Glomerulus/metabolism Male *Mechanotransduction, Cellular Mice Phosphoproteins/genetics/*metabolism Podocytes/cytology/drug effects/*metabolism Proteinuria/genetics/metabolism Proteomics Puromycin Aminonucleoside/pharmacology Rats Stress, Mechanical Transcription Factors/genetics/*metabolism
 要旨: 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.

資料詳細

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 日付: 2017
 出版の状態: 出版
 ページ: -
 出版情報: -
 目次: -
 査読: -
 識別子（DOI, ISBNなど）: その他: 28400537
DOI: 10.1126/scisignal.aaf8165
ISSN: 1937-9145 (Electronic)1945-0877 (Linking)
 学位: -

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出版物 1

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出版物名: Sci Signal
種別: 学術雑誌
 著者・編者:
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出版社, 出版地: -
ページ: - 巻号: 10 (474) 通巻号: - 開始・終了ページ: - 識別子（ISBN, ISSN, DOIなど）: -