Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans
Bernhard Bielesz, Yasemin Sirin, Han Si, Thiruvur Niranjan, Antje Gruenwald, Seonho Ahn, Hideki Kato, James Pullman, Manfred Gessler, Volker H. Haase, Katalin Susztak
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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Research Article Nephrology

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 1

Increased expression of Notch pathway in kidneys of mouse models of TIF and patients with TIF.

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Increased expression of Notch pathway in kidneys of mouse models of TIF ...
(A) Relative mRNA amount of Notch1, Notch2, Notch3, Jag1, Dll1, Dll4, Hes1, and HeyL determined by QRT-PCR in FA-injected (10-week-old male FvB) mice 1, 3, 5, 7, and 14 days following the injection. Kidneys were isolated individually from each animal sacrificed at different time points after FA injection (n > 3 per time point). Gene expression level was normalized to mRNA levels of control animals, and significance was calculated compared with controls. (B) Representative immunostaining images of cleaved Notch1–stained kidney sections of control and FA-injected mice. ICN1 expression in FA-treated kidneys increased compared with controls. (C) Double immunofluorescence analysis with Jag1 (Cy3, red) and Lotus Tetragonolobus lectin (LTL; FITC, green) of control and 1 week after FA treatment. Jag1 expression increased after FA injection compared with control animals. (D and E) Representative images of (D) cleaved NOTCH1 and (E) JAG1 immunostaining from a control healthy individual and from a patient with diabetic kidney disease (DKD) with marked TIF. *P < 0.05, Student’s t test with Bonferroni correction. Scale bars: 20 μm (B, left, and D, right), 10 μm (B, right), 50 μm (C, D, left, and E).