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J Clin Invest. 2010 Nov;120(11):4040-54. doi: 10.1172/JCI43025. Epub 2010 Oct 18.

Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans.

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1
Department of Medicine, Division of Nephrology, Albert Einstein College of Medicine, New York, New York 10461, USA.

Abstract

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.

PMID:
20978353
PMCID:
PMC2964979
DOI:
10.1172/JCI43025
[Indexed for MEDLINE]
Free PMC Article

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