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

Abstract

PGC‐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.

PGC-1α, Inflammation, and Oxidative Stress: An Integrative View in Metabolism

“…It has been previously reported that the severity of sepsis-associated acute kidney injury (AKI) correlates with PGC-1α levels in the kidney, and accordingly, lack of PGC-1α causes persistent kidney injury following endotoxemia [128]. In fact under the basal condition, PGC-1α KO mice display spontaneous subclinical kidney injury characterized by tubulointerstitial inflammation and exhibit a higher mortality rate than their wild-type (WT) littermates after AKI induction [129]. In addition, the expression of PGC-1α diminishes in aging muscle and has been associated with systemic inflammation in mice [130].…”

“…After LPS/TNFα injection, the overexpression of PGC-1α in skeletal muscle does not suppress proinflammatory cytokine expression but lowers M1 cytokine IL-12 levels and enhances the production of anti-inflammatory M2 cytokines [142]. In addition, PGC-1α KO mice exhibit increased M1 and decreased M2 responses in the kidney after AKI induction [129]. Although the molecular mechanisms regulating macrophages polarization are poorly understood, these cells have been reported to be metabolically reprogrammed during polarization [143].…”

The Contribution of Histone Crotonylation to Tissue Health and Disease: Focus on Kidney Health

“…acetylation but may in fact be related to increase histone crotonylation include preservation of the expression of the antiaging and nephroprotective gene Klotho despite the presence of Klotho suppressors such as inflammatory cytokines and albuminuria, and similar results were observed with PGC1a expression (Chen et al, 2018;Fernandez-Fernandez et al, 2018;Fontecha-Barriuso et al, 2019). This hypothesis should be addressed through specifically designed experiments.…”

“…The increased histone crotonylation in cells stimulated with TWEAK and in AKI kidneys was associated with decreased PGC1a and Sirt-3 expression and with increased CCL2 expression, a chemokine which contributes to kidney inflammation (Ruiz-Andres et al, 2016a). PGC1a and Sirt-3 have nephroprotective actions (Kong et al, 2010;Morigi et al, 2015;Fontecha-Barriuso et al, 2019). Besides, Sirt3 and PGC1a regulate each other.…”

“…decreased expression of the master regulator of mitochondrial biogenesis PGC1a or sirtuin 3, Sirt3) kidney cell injury and elicit a proinflammatory response (e.g. chemokine synthesis) (Morigi et al, 2015;Martin-Sanchez et al, 2018;Fontecha-Barriuso et al, 2019). (B) This will induce kidney injury that may be magnified by recruitment of inflammatory cells (Ruiz-Andres et al, 2016b).…”