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

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