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PGC-1α Protects from Notch-Induced Kidney Fibrosis Development

Authors
 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 
Citation
 Journal of the American Society of Nephrology, Vol.28(11) : 3312-3322, 2017 
Journal Title
 Journal of the American Society of Nephrology 
ISSN
 1046-6673 
Issue Date
2017
MeSH
Animals ; Fibrosis/etiology ; Humans ; Kidney/pathology* ; Mice ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/physiology* ; Receptor, Notch1/physiology* ; Receptors, Notch/physiology* ; Transcription Factors/physiology*
Keywords
Notch ; PGC-1α ; fatty acid oxidation ; kidney fibrosis ; mitochondria
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-1α) and fatty acid oxidation-related genes are lower in mice 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-1α 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-1α restored mitochondrial content and reversed the fatty acid oxidation defect induced by Notch 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-1α.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/161274
DOI
10.1681/ASN.2017020130
Appears in Collections:
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실)
Yonsei Authors
강신욱(Kang, Shin Wook) ; 박정탁(Park, Jung Tak) ; 유태현(Yoo, Tae Hyun) ; 한승혁(Han, Seung Hyeok)
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Full Text
http://jasn.asnjournals.org/content/28/11/3312.long
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