| First Author | Fontecha-Barriuso M | Year | 2019 |
| Journal | J Pathol | Volume | 249 |
| Issue | 1 | Pages | 65-78 |
| PubMed ID | 30982966 | Mgi Jnum | J:279370 |
| Mgi Id | MGI:6362308 | Doi | 10.1002/path.5282 |
| Citation | Fontecha-Barriuso M, et al. (2019) PGC-1alpha deficiency causes spontaneous kidney inflammation and increases the severity of nephrotoxic AKI. J Pathol 249(1):65-78 |
| abstractText | PGC-1alpha (peroxisome proliferator-activated receptor gamma coactivator-1alpha, PPARGC1A) regulates the expression of genes involved in energy homeostasis and mitochondrial biogenesis. Here we identify inactivation of the transcriptional regulator PGC-1alpha as a landmark for experimental nephrotoxic acute kidney injury (AKI) and describe the in vivo consequences of PGC-1alpha deficiency over inflammation and cell death in kidney injury. Kidney transcriptomic analyses of WT mice with folic acid-induced AKI revealed 1398 up- and 1627 downregulated genes. Upstream transcriptional regulator analyses pointed to PGC-1alpha as the transcription factor potentially driving the observed expression changes with the highest reduction in activity. Reduced PGC-1alpha expression was shared by human kidney injury. Ppargc1a(-/-) mice had spontaneous subclinical kidney injury characterized by tubulointerstitial inflammation and increased Ngal expression. Upon AKI, Ppargc1a(-/-) mice had lower survival and more severe loss of renal function, tubular injury, and reduction in expression of mitochondrial PGC-1alpha-dependent genes in the kidney, and an earlier decrease in mitochondrial mass than WT mice. Additionally, surviving Ppargc1a(-/-) mice showed higher rates of tubular cell death, compensatory proliferation, expression of proinflammatory cytokines, NF-kappaB activation, and interstitial inflammatory cell infiltration. Specifically, Ppargc1a(-/-) mice displayed increased M1 and decreased M2 responses and expression of the anti-inflammatory cytokine IL-10. In cultured renal tubular cells, PGC-1alpha targeting promoted spontaneous cell death and proinflammatory responses. In conclusion, PGC-1alpha inactivation is a key driver of the gene expression response in nephrotoxic AKI and PGC-1alpha deficiency promotes a spontaneous inflammatory kidney response that is magnified during AKI. (c) 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. |
