PGC-1α deficiency causes spontaneous kidney inflammation and increases the severity of nephrotoxic AKI

PGC-1 alpha (peroxisome proliferator-activated receptor gamma coactivator-1 alpha, PPARGC1A) regulates the expression of genes involved in energy homeostasis and mitochondrial biogenesis. Here we identify inactivation of the transcriptional regulator PGC-1 alpha as a landmark for experimental nephrotoxic acute kidney injury (AKI) and describe the in vivo consequences of PGC-1 alpha 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-1 alpha as the transcription factor potentially driving the observed expression changes with the highest reduction in activity. Reduced PGC-1 alpha 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-1 alpha-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-kappa B 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-1 alpha targeting promoted spontaneous cell death and proinflammatory responses. In conclusion, PGC-1 alpha inactivation is a key driver of the gene expression response in nephrotoxic AKI and PGC-1 alpha 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.