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 M. Pullman, Manfred Gessler, Volker H. Haase, Katalin Susztak

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)4040-4054
Number of pages15
JournalJournal of Clinical Investigation
Volume120
Issue number11
DOIs
StatePublished - Nov 1 2010

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Fibrosis
Kidney
Epithelial Cells
Chronic Kidney Failure
Amyloid Precursor Protein Secretases
Chronic Renal Insufficiency
Cause of Death
Wounds and Injuries

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Bielesz, B., Sirin, Y., Si, H., Niranjan, T., Gruenwald, A., Ahn, S., ... Susztak, K. (2010). Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans. Journal of Clinical Investigation, 120(11), 4040-4054. https://doi.org/10.1172/JCI43025

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

In: Journal of Clinical Investigation, Vol. 120, No. 11, 01.11.2010, p. 4040-4054.

Research output: Contribution to journalArticle

Bielesz, B, Sirin, Y, Si, H, Niranjan, T, Gruenwald, A, Ahn, S, Kato, H, Pullman, JM, Gessler, M, Haase, VH & Susztak, K 2010, 'Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans', Journal of Clinical Investigation, vol. 120, no. 11, pp. 4040-4054. https://doi.org/10.1172/JCI43025
Bielesz, Bernhard ; Sirin, Yasemin ; Si, Han ; Niranjan, Thiruvur ; Gruenwald, Antje ; Ahn, Seonho ; Kato, Hideki ; Pullman, James M. ; Gessler, Manfred ; Haase, Volker H. ; Susztak, Katalin. / Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans. In: Journal of Clinical Investigation. 2010 ; Vol. 120, No. 11. pp. 4040-4054.
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