Document Detail

Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans.
MedLine Citation:
PMID:  20978353     Owner:  NLM     Status:  MEDLINE    
Chronic kidney disease is a leading cause of death in the United States. Tubulointerstitial fibrosis (TIF) is considered the final common pathway leading to end-stage renal disease (ESRD). Here, we used pharmacologic, genetic, in vivo, and in vitro experiments to show that activation of the Notch pathway in tubular epithelial cells (TECs) in patients and in mouse models of TIF plays a role in TIF development. Expression of Notch in renal TECs was found to be both necessary and sufficient for TIF development. Genetic deletion of the Notch pathway in TECs reduced renal fibrosis. Consistent with this, TEC-specific expression of active Notch1 caused rapid development of TIF. Pharmacologic inhibition of Notch activation using a γ-secretase inhibitor ameliorated TIF. In summary, our experiments establish that epithelial injury and Notch signaling play key roles in fibrosis development and indicate that Notch blockade may be a therapeutic strategy to reduce fibrosis and ESRD development.
Bernhard Bielesz; Yasemin Sirin; Han Si; Thiruvur Niranjan; Antje Gruenwald; Seonho Ahn; Hideki Kato; James Pullman; Manfred Gessler; Volker H Haase; Katalin Susztak
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-10-18
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  120     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-11-02     Completed Date:  2010-12-07     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4040-54     Citation Subset:  AIM; IM    
Department of Medicine, Division of Nephrology, Albert Einstein College of Medicine, New York, New York 10461, USA.
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MeSH Terms
Amyloid Precursor Protein Secretases / antagonists & inhibitors
Basic Helix-Loop-Helix Transcription Factors / genetics,  metabolism
Calcium-Binding Proteins / genetics,  metabolism
Cell Proliferation
Epithelial Cells / cytology,  metabolism*
Fibrosis / pathology
Homeodomain Proteins / genetics,  metabolism
Intercellular Signaling Peptides and Proteins / genetics,  metabolism
Kidney / cytology,  metabolism*,  pathology*
Kidney Failure, Chronic / metabolism,  pathology
Kidney Tubules / cytology*
Membrane Proteins / genetics,  metabolism
Mice, Transgenic
Nephritis, Interstitial / metabolism,  pathology
Receptor, Notch1 / genetics,  metabolism*
Signal Transduction / physiology*
Grant Support
5R01DK076077/DK/NIDDK NIH HHS; R01 DK076077-04/DK/NIDDK NIH HHS; R01 DK076077-05/DK/NIDDK NIH HHS; R01 DK081646/DK/NIDDK NIH HHS
Reg. No./Substance:
0/Basic Helix-Loop-Helix Transcription Factors; 0/Calcium-Binding Proteins; 0/Hes1 protein, mouse; 0/Heyl protein, mouse; 0/Homeodomain Proteins; 0/Intercellular Signaling Peptides and Proteins; 0/Membrane Proteins; 0/NOTCH1 protein, human; 0/Notch1 protein, mouse; 0/Receptor, Notch1; 134324-36-0/Serrate proteins; EC 3.4.-/Amyloid Precursor Protein Secretases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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