Orphan nuclear receptor ERR-γ regulates hepatic FGF23 production in acute kidney injury

Proc Natl Acad Sci U S A. 2021 Apr 20;118(16):e2022841118. doi: 10.1073/pnas.2022841118.


Fibroblast growth factor 23 (FGF23), a hormone generally derived from bone, is important in phosphate and vitamin D homeostasis. In acute kidney injury (AKI) patients, high-circulating FGF23 levels are associated with disease progression and mortality. However, the organ and cell type of FGF23 production in AKI and the molecular mechanism of its excessive production are still unidentified. For insight, we investigated folic acid (FA)-induced AKI in mice. Interestingly, simultaneous with FGF23, orphan nuclear receptor ERR-γ expression is increased in the liver of FA-treated mice, and ectopic overexpression of ERR-γ was sufficient to induce hepatic FGF23 production. In patients and in mice, AKI is accompanied by up-regulated systemic IL-6, which was previously identified as an upstream regulator of ERR-γ expression in the liver. Administration of IL-6 neutralizing antibody to FA-treated mice or of recombinant IL-6 to healthy mice confirms IL-6 as an upstream regulator of hepatic ERR-γ-mediated FGF23 production. A significant (P < 0.001) interconnection between high IL-6 and FGF23 levels as a predictor of AKI in patients that underwent cardiac surgery was also found, suggesting the clinical relevance of the finding. Finally, liver-specific depletion of ERR-γ or treatment with an inverse ERR-γ agonist decreased hepatic FGF23 expression and plasma FGF23 levels in mice with FA-induced AKI. Thus, inverse agonist of ERR-γ may represent a therapeutic strategy to reduce adverse plasma FGF23 levels in AKI.

Keywords: ERR-γ; FGF23; acute kidney injury; interleukin 6; orphan nuclear receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / metabolism
  • Acute Kidney Injury / physiopathology*
  • Animals
  • Disease Models, Animal
  • Fibroblast Growth Factor-23 / genetics
  • Fibroblast Growth Factor-23 / metabolism*
  • Folic Acid / adverse effects
  • Folic Acid / pharmacology
  • Interleukin-6 / metabolism
  • Kidney / metabolism
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Orphan Nuclear Receptors / metabolism
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism*
  • Transcriptional Activation


  • Esrrg protein, mouse
  • Fgf23 protein, mouse
  • Interleukin-6
  • Orphan Nuclear Receptors
  • Receptors, Estrogen
  • Fibroblast Growth Factor-23
  • Folic Acid