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

• DOI: 10.1681/asn.2017020130
• Publication Date: 2017-07-28T00:50:25Z
• 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
• Keywords: 570; Notch; Receptors, Notch; Notch1/physiology*; Notch/physiology*; kidney fibrosis; PGC-1α; 610; Kidney/pathology*; Kidney; Fibrosis; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Transcription Factors/physiology*; mitochondria; Mice; Receptors; Animals; Humans; Fibrosis/etiology; Receptor, Notch1; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/physiology*; fatty acid oxidation; Receptor; Transcription Factors

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.