Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans
Bernhard Bielesz, … , Volker H. Haase, Katalin Susztak
Bernhard Bielesz, … , Volker H. Haase, Katalin Susztak
Published October 18, 2010
Citation Information: J Clin Invest. 2010;120(11):4040-4054. https://doi.org/10.1172/JCI43025.
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Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans

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.

Authors

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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Figure 6

Transgenic expression of ICNotch1 in TECs causes severe kidney fibrosis.

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Transgenic expression of ICNotch1 in TECs causes severe kidney fibrosis....
(A) Relative mRNA amount of Notch targets Hes1, Hey1, and HeyL and (C) Fn1, Col1a1, Col3a1, Col4a1, Vim, Acta2, Cd68, and Emr1 in doxycycline-fed wild-type and single-transgenic controls and double-transgenic Pax8rtTA/ICNotch1 animals. Relative mRNA amount was normalized to the expression levels in control animals. (B) Representative images of PAS-stained kidney sections from wild-type and single-transgenic control and double-transgenic Pax8rtTA/ICNotch1 animals. Male littermates were placed on doxycycline containing food at 4 weeks of age and sacrificed at 8 weeks of age (n > 5 per group). Scale bars: 100 μm (B, top), 50 μm (B, middle and bottom).