PGC-1<i>α</i> Protects from Notch-Induced Kidney Fibrosis Development.

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-1<i>α</i>) and fatty acid oxidation-related genes are lower in mice expressing active Notch1 in tubular epithelial cells (Pax8-rtTA/<i>ICN1</i>) compared to littermate controls. Chromatin immunoprecipitation assays revealed that the Notch target gene <i>Hes1</i> directly binds to the regulatory region of PGC-1<i>α</i> Compared with <i>Pax8-rtTA/ICN1</i> transgenic animals, <i>Pax8-rtTA/ICN1/Ppargc1a</i> transgenic mice showed improvement of renal structural alterations (on histology) and molecular defect (expression of profibrotic genes). Overexpression of PGC-1<i>α</i> restored mitochondrial content and reversed the fatty acid oxidation defect induced by Notch overexpression <i>in vitro</i> in tubule cells. Furthermore, compared with <i>Pax8-rtTA/ICN1</i> mice, <i>Pax8-rtTA/ICN1/Ppargc1a</i> 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-1<i>α</i>.