Glycerol-3-phosphate is an FGF23 regulator derived from the injured kidney

J Clin Invest. 2020 Mar 2;130(3):1513-1526. doi: 10.1172/JCI131190.

Abstract

Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that controls blood phosphate levels by increasing renal phosphate excretion and reducing 1,25-dihydroxyvitamin D3 [1,25(OH)2D] production. Disorders of FGF23 homeostasis are associated with significant morbidity and mortality, but a fundamental understanding of what regulates FGF23 production is lacking. Because the kidney is the major end organ of FGF23 action, we hypothesized that it releases a factor that regulates FGF23 synthesis. Using aptamer-based proteomics and liquid chromatography-mass spectrometry-based (LC-MS-based) metabolomics, we profiled more than 1600 molecules in renal venous plasma obtained from human subjects. Renal vein glycerol-3-phosphate (G-3-P) had the strongest correlation with circulating FGF23. In mice, exogenous G-3-P stimulated bone and bone marrow FGF23 production through local G-3-P acyltransferase-mediated (GPAT-mediated) lysophosphatidic acid (LPA) synthesis. Further, the stimulatory effect of G-3-P and LPA on FGF23 required LPA receptor 1 (LPAR1). Acute kidney injury (AKI), which increases FGF23 levels, rapidly increased circulating G-3-P in humans and mice, and the effect of AKI on FGF23 was abrogated by GPAT inhibition or Lpar1 deletion. Together, our findings establish a role for kidney-derived G-3-P in mineral metabolism and outline potential targets to modulate FGF23 production during kidney injury.

Keywords: Bone Biology; Bone disease; Chronic kidney disease; Homeostasis; Nephrology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / genetics
  • Acute Kidney Injury / metabolism*
  • Acute Kidney Injury / pathology
  • Animals
  • Cell Line
  • Female
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism*
  • Glycerophosphates / metabolism*
  • Humans
  • Kidney / metabolism*
  • Kidney / pathology
  • Male
  • Metabolomics
  • Mice
  • Mice, Knockout
  • Receptors, Lysophosphatidic Acid / genetics
  • Receptors, Lysophosphatidic Acid / metabolism

Substances

  • Glycerophosphates
  • LPAR1 protein, human
  • Receptors, Lysophosphatidic Acid
  • lysophosphatidic acid receptor 1, mouse
  • Fibroblast Growth Factors
  • fibroblast growth factor 23
  • alpha-glycerophosphoric acid