| First Author | Huang Y | Year | 2020 |
| Journal | Nat Commun | Volume | 11 |
| Issue | 1 | Pages | 4664 |
| PubMed ID | 32938919 | Mgi Jnum | J:297027 |
| Mgi Id | MGI:6468878 | Doi | 10.1038/s41467-020-18519-0 |
| Citation | Huang Y, et al. (2020) IRF1-mediated downregulation of PGC1alpha contributes to cardiorenal syndrome type 4. Nat Commun 11(1):4664 |
| abstractText | Cardiorenal syndrome type 4 (CRS4) is a common complication of chronic kidney disease (CKD), but the pathogenic mechanisms remain elusive. Here we report that morphological and functional changes in myocardial mitochondria are observed in CKD mice, especially decreases in oxidative phosphorylation and fatty acid metabolism. High phosphate (HP), a hallmark of CKD, contributes to myocardial energy metabolism dysfunction by downregulating peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1alpha). Furthermore, the transcriptional factor interferon regulatory factor 1 (IRF1) is revealed as the key molecule upregulated by HP through histone H3K9 acetylation, and responsible for the HP-mediated transcriptional inhibition of PGC1alpha by directly binding to its promoter region. Conversely, restoration of PGC1alpha expression or genetic knockdown of IRF1 significantly attenuates HP-induced alterations in vitro and in vivo. These findings demonstrate that IRF1-PGC1alpha axis-mediated myocardial energy metabolism remodeling plays a crucial role in the pathogenesis of CRS4. |
