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

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 kid...

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Published in:The Journal of pathology 2019-09, Vol.249 (1), p.65-78
Main Authors: Fontecha‐Barriuso, Miguel, Martín‐Sánchez, Diego, Martinez‐Moreno, Julio M, Carrasco, Susana, Ruiz‐Andrés, Olga, Monsalve, Maria, Sanchez‐Ramos, Cristina, Gómez, Manuel J, Ruiz‐Ortega, Marta, Sánchez‐Niño, Maria D, Cannata‐Ortiz, Pablo, Cabello, Ramiro, Gonzalez‐Enguita, Carmen, Ortiz, Alberto, Sanz, Ana B
Format: Article
Language:English
Subjects:
acute kidney injury
Acute Kidney Injury - chemically induced
Acute Kidney Injury - genetics
Acute Kidney Injury - metabolism
Acute Kidney Injury - pathology
Animals
Apoptosis
Cell activation
Cell Death
Cell Line
Cell Proliferation
Cytokines
Cytokines - metabolism
Disease Models, Animal
Energy balance
Female
Folic Acid
Gene expression
Genes
Homeostasis
Humans
Inactivation
Inflammation
Inflammation Mediators - metabolism
Injury analysis
Kidney - metabolism
Kidney - pathology
Kidney - physiopathology
Kidneys
Lipocalin-2 - genetics
Lipocalin-2 - metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondria
Mitochondria - genetics
Mitochondria - metabolism
Mitochondria - pathology
Nephritis, Interstitial - genetics
Nephritis, Interstitial - metabolism
Nephritis, Interstitial - pathology
Nephritis, Interstitial - physiopathology
Organelle Biogenesis
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - deficiency
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - genetics
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism
PGC‐1α
proximal tubule
Renal function
Severity of Illness Index
Signal Transduction
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Summary: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.
ISSN:0022-3417
1096-9896
DOI:10.1002/path.5282