| First Author | Han SH | Year | 2017 |
| Journal | J Am Soc Nephrol | Volume | 28 |
| Issue | 11 | Pages | 3312-3322 |
| PubMed ID | 28751525 | Mgi Jnum | J:290340 |
| Mgi Id | MGI:6435940 | Doi | 10.1681/ASN.2017020130 |
| Citation | Han SH, et al. (2017) PGC-1alpha Protects from Notch-Induced Kidney Fibrosis Development. J Am Soc Nephrol 28(11):3312-3322 |
| abstractText | 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-1alpha) 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-1alpha 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-1alpha 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-1alpha. |
