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Abstract: SA-OR098

Glycerol-3-Phosphate Is a Novel FGF23 Regulator Derived from the Injured Kidney

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Simic, Petra, Massachusetts General Hospital, Brookline, Massachusetts, United States
  • Kim, Wondong, Massachusetts General Hospital, Brookline, Massachusetts, United States
  • Kestenbaum, Bryan R., University of Washington, Seattle, Washington, United States
  • de Boer, Ian H., Division of Nephrology and Kidney Research Institute, University of Washington, Seattle, Washington, United States
  • Leaf, David E., Harvard Medical School, Boston, Massachusetts, United States
  • Waikar, Sushrut S., Harvard Medical School, Boston, Massachusetts, United States
  • Gerszten, Robert, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
  • Thadhani, Ravi I., Cedars-Sinai, Los Angeles, California, United States
  • Clish, Clary B., Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States
  • Jüppner, Harald, Massachusetts General Hospital, Brookline, Massachusetts, United States
  • Wein, Marc N., MGH Endocrine Unit, Boston, Massachusetts, United States
  • Rhee, Eugene P., Massachusetts General Hospital, Brookline, Massachusetts, United States
Background

Disorders of FGF23 are associated with significant morbidity and mortality, but an understanding of what regulates FGF23 in bone is lacking. Because the kidney is the major end-organ of FGF23 action, we hypothesized that it releases a factor that regulates bone FGF23 synthesis.

Methods

Using aptamer based proteomics and liquid chromatography-mass spectrometry (LC-MS) based metabolomics, we profiled >1600 molecules in renal venous plasma obtained from human subjects. After identifying the molecule that has the strongest correlation with FGF23, we used in vitro techniques and genetically modified mice to investigate its effects on bone FGF23 production. Further, we examined the association between the molecule and FGF23 levels in an ischemia-reperfusion (IRI) model of acute kidney injury (AKI) in mice, and in 26 individuals who did (cases) or did not (controls) develop AKI after cardiac surgery.

Results

Renal vein glycerol-3-phosphate (G-3-P) had the strongest correlation with circulating intact FGF23 (iFGF23) levels (r2 = 0.76, P = 5.2x10-6) in humans. Injection of G-3-P, as well as its downstream product lysophosphatidic acid (LPA) in mice increased plasma iFGF23 and c-terminal FGF23 (cFGF23) levels at 24 hours. G-3-P increased LPA levels in bone marrow and in osteoblast cell culture, and this effect on LPA as well as G-3-P’s stimulatory effect on FGF23 production, were blocked with the glycerol-3-phosphate acyltransferase (GPAT) inhibitor FSG67 in vivo and Gpat2 knock-down in vitro. The stimulatory effect of G-3-P and LPA on FGF23 production were similarly abrogated in Lpar1 deficient cells and mice. In mice subjected to IRI, kidney tissue G-3-P levels rose rapidly; the increase in iFGF23 levels following IRI was significantly attenuated with GPAT inhibition or Lpar1 deletion. In humans undergoing cardiac surgery, plasma G-3-P levels increased significantly and correlated with the plasma iFGF23 levels (r2 = 0.31) in AKI cases but not controls.

Conclusion

Our findings establish G-3-P as a molecule released from the injured kidney, that is converted to LPA via GPAT-2 in bone where it triggers FGF23 production through LPAR1. This is a novel mechanism in mineral metabolism and outlines potential targets to modulate FGF23 production during kidney injury.

Funding

  • NIDDK Support