Glycerol-3-phosphate is an FGF23 regulator derived from the injured kidney
Petra Simic, … , Marc N. Wein, Eugene P. Rhee
Petra Simic, … , Marc N. Wein, Eugene P. Rhee
Published February 17, 2020
Citation Information: J Clin Invest. 2020;130(3):1513-1526. https://doi.org/10.1172/JCI131190.
View: Text | PDF
Research Article Bone biology Nephrology

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

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.

Authors

Petra Simic, Wondong Kim, Wen Zhou, Kerry A. Pierce, Wenhan Chang, David B. Sykes, Najihah B. Aziz, Sammy Elmariah, Debby Ngo, Paola Divieti Pajevic, Nicolas Govea, Bryan R. Kestenbaum, Ian H. de Boer, Zhiqiang Cheng, Marta Christov, Jerold Chun, David E. Leaf, Sushrut S. Waikar, Andrew M. Tager, Robert E. Gerszten, Ravi I. Thadhani, Clary B. Clish, Harald Jüppner, Marc N. Wein, Eugene P. Rhee

×

Figure 1

Screen of human renal venous plasma highlights the association between G-3-P and arterial FGF23.

Options: View larger image (or click on image) Download as PowerPoint
Screen of human renal venous plasma highlights the association between G...
(A) Study overview demonstrating arterial and renal venous plasma sampling with subsequent measurement of iFGF23, creatinine, and phosphate as well as proteomic and metabolomic profiling. (B and C) Cystatin C measured by aptamer (B) and creatinine measured by LC-MS (C) in the artery (A) and renal vein (V) of all individuals (n = 17). (D) Scatter plot with each molecule measured by aptamer or LC-MS in the renal vein samples (proteins in blue, metabolites in red, unknown LC-MS peaks, no color). Molecules are plotted along the y axis based on r2 with arterial iFGF23 and along the x axis based on the median V/A ratio of the molecule. Dotted lines show the median V/A ratio for cystatin C and creatinine. (E) Graph showing the V/A ratio for select proteins and metabolites, with each individual depicted by a separate vertical line. Median V/A ratios for the select proteins and metabolites are shown below the graph. P values were determined by 2-sided, paired t test. Epo, erythropoietin. (F–H) Scatter plots showing correlations between arterial iFGF23 and renal vein G-3-P (F), arterial phosphate (G), and eGFR (H).