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J Am Soc Nephrol. 2017 Nov;28(11):3312-3322. doi: 10.1681/ASN.2017020130. Epub 2017 Jul 27.

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

Author information

1
Department of Internal Medicine, Institute of Kidney Disease Research, Yonsei University College of Medicine, Seoul, Korea.
2
Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
3
Severance Biomedical Science Institute, Brain Korea 21 PLUS, Yonsei University College of Medicine, Seoul, Korea; and.
4
Department of Nephrology, The First Hospital of Jilin University, Changchun, China.
5
Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; ksusztak@mail.med.upenn.edu.

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.

KEYWORDS:

Notch; PGC-1α; fatty acid oxidation; kidney fibrosis; mitochondria

PMID:
28751525
PMCID:
PMC5661291
DOI:
10.1681/ASN.2017020130
[Indexed for MEDLINE]
Free PMC Article

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