PGC-1a protects from notch-induced kidney fibrosis development

Seung Hyeok Han, Mei Yan Wu, Bo Young Nam, Jung Tak Park, Tae Hyun Yoo, Shin Wook Kang, Jihwan Park, Frank Chinga, Szu Yuan Li, Katalin Susztak

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Kidney fibrosis is the histologic manifestation of CKD. Sustained activation of developmental pathways, such as Notch, in tubule epithelial cells has been shown to have a key role in fibrosis development. The molecular mechanism of Notch-induced fibrosis, however, remains poorly understood. Here, we show that, that expression of peroxisomal proliferation g-coactivator (PGC-1a) and fatty acid oxidation-related genes are lower inmice expressing active Notch1 in tubular epithelial cells (Pax8-rtTA/ICN1) compared to littermate controls. Chromatin immunoprecipitation assays revealed that the Notch target gene Hes1 directly binds to the regulatory region of PGC-1a. Compared with Pax8-rtTA/ICN1 transgenic animals, Pax8-rtTA/ICN1/Ppargc1a transgenic mice showed improvement of renal structural alterations (on histology) and molecular defect (expression of profibrotic genes). Overexpression of PGC-1a restored mitochondrial content and reversed the fatty acid oxidation defect induced byNotch overexpression in vitro in tubule cells. Furthermore, compared with Pax8-rtTA/ICN1 mice, Pax8-rtTA/ICN1/Ppargc1a mice exhibited improvement in renal fatty acid oxidation gene expression and apoptosis. Our results show that metabolic dysregulation has a key role in kidney fibrosis induced by sustained activation of the Notch developmental pathway and can be ameliorated by PGC-1a.

Original languageEnglish
Pages (from-to)3312-3322
Number of pages11
JournalJournal of the American Society of Nephrology
Volume28
Issue number11
DOIs
Publication statusPublished - 2017 Nov

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All Science Journal Classification (ASJC) codes

  • Nephrology

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