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

J Pathol. 2019 Sep;249(1):65-78. doi: 10.1002/path.5282. Epub 2019 Jun 12.

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.

Keywords: PGC-1α; acute kidney injury; cell death; inflammation; mitochondria; proximal tubule.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / chemically induced
  • Acute Kidney Injury / genetics
  • Acute Kidney Injury / metabolism*
  • Acute Kidney Injury / pathology
  • Animals
  • Cell Death
  • Cell Line
  • Cell Proliferation
  • Cytokines / metabolism
  • Disease Models, Animal
  • Female
  • Folic Acid
  • Humans
  • Inflammation Mediators / metabolism
  • Kidney / metabolism*
  • Kidney / pathology
  • Kidney / physiopathology
  • Lipocalin-2 / genetics
  • Lipocalin-2 / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • 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
  • Severity of Illness Index
  • Signal Transduction

Substances

  • Cytokines
  • Inflammation Mediators
  • Lipocalin-2
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Lcn2 protein, mouse
  • Folic Acid