Glycerol-3-phosphate is an FGF23 regulator derived from the injured kidney
- Authors
- Simic, Petra; Kim, Wondong; Zhou, Wen; Pierce, Kerry A.; Chang, Wenhan; Sykes, David B.; Aziz, Najihah B.; Elmariah, Sammy; Ngo, Debby; Pajevic, Paola Divieti; Govea, Nicolas; Kestenbaum, Bryan R.; De Boer, Ian H.; Cheng, Zhiqiang; Christov, Marta; Chun, Jerold; Leaf, David E.; Waikar, Sushrut S.; Tager, Andrew M.; Gerszten, Robert E.; Thadhani, Ravi I.; Clish, Clary B.; Jüppner, Harald; Wein, Marc N.; Rhee, Eugene P.
- Issue Date
- Mar-2020
- Publisher
- American Society for Clinical Investigation
- Citation
- Journal of Clinical Investigation, v.130, no.3, pp 1513 - 1526
- Pages
- 14
- Indexed
- SCIE
SCOPUS
- Journal Title
- Journal of Clinical Investigation
- Volume
- 130
- Number
- 3
- Start Page
- 1513
- End Page
- 1526
- URI
- https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/113943
- DOI
- 10.1172/JCI131190
- ISSN
- 0021-9738
1558-8238
- 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. © 2020, American Society for Clinical Investigation.
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