Fontecha-Barriuso, MiguelMartín-Sánchez, DiegoMartinez-Moreno, Julio MCarrasco, SusanaRuiz-Andrés, OlgaMonsalve, MariaSanchez-Ramos, CristinaGómez, Manuel JRuiz-Ortega, MartaSánchez-Niño, Maria DCannata-Ortiz, PabloCabello, RamiroGonzalez-Enguita, CarmenOrtiz, AlbertoSanz, Ana B2024-01-312024-01-312019-09J Pathol. 2019 Sep;249(1):65-78.http://hdl.handle.net/20.500.12105/17396PGC-1α (peroxisome proliferator-activated receptor gamma coactivator-1α, PPARGC1A) regulates the expression of genes involved in energy homeostasis and mitochondrial biogenesis. Here we identify inactivation of the transcriptional regulator PGC-1α as a landmark for experimental nephrotoxic acute kidney injury (AKI) and describe the in vivo consequences of PGC-1α 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-1α as the transcription factor potentially driving the observed expression changes with the highest reduction in activity. Reduced PGC-1α 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-1α-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-κB 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-1α targeting promoted spontaneous cell death and proinflammatory responses. In conclusion, PGC-1α inactivation is a key driver of the gene expression response in nephrotoxic AKI and PGC-1α deficiency promotes a spontaneous inflammatory kidney response that is magnified during AKI. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/Acute Kidney InjuryAnimalsCell DeathCell LineCell ProliferationCytokinesDisease Models, AnimalFemaleFolic AcidHumansInflammation MediatorsKidneyLipocalin-2Mice, Inbred C57BLMice, KnockoutMitochondriaNephritis, InterstitialOrganelle BiogenesisPeroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alphaSeverity of Illness IndexSignal TransductionAttribution-NonCommercial-NoDerivatives 4.0 Internacional3098296624916510.1002/path.52821096-9896The Journal of pathologyopen access