Kidney glycolysis serves as a mammalian phosphate sensor that maintains phosphate homeostasis.

Content Provider	Europe PMC
Author	Zhou, Wen Simic, Petra Zhou, Iris Y. Caravan, Peter Vela Parada, Xavier Wen, Donghai Washington, Onica L. Shvedova, Maria Pierce, Kerry A. Clish, Clary B. Mannstadt, Michael Kobayashi, Tatsuya Wein, Marc N. Jüppner, Harald Rhee, Eugene P.
Copyright Year	2023
Abstract	How phosphate levels are detected in mammals is unknown. The bone-derived hormone fibroblast growth factor 23 (FGF23) lowers blood phosphate levels by reducing kidney phosphate reabsorption and 1,25(OH)2D production, but phosphate does not directly stimulate bone FGF23 expression. Using PET scanning and LC-MS, we found that phosphate increases kidney-specific glycolysis and synthesis of glycerol-3-phosphate (G-3-P), which then circulates to bone to trigger FGF23 production. Further, we found that G-3-P dehydrogenase 1 (Gpd1), a cytosolic enzyme that synthesizes G-3-P and oxidizes NADH to NAD+, is required for phosphate-stimulated G-3-P and FGF23 production and prevention of hyperphosphatemia. In proximal tubule cells, we found that phosphate availability is substrate-limiting for glycolysis and G-3-P production and that increased glycolysis and Gpd1 activity are coupled through cytosolic NAD+ recycling. Finally, we show that the type II sodium-dependent phosphate cotransporter Npt2a, which is primarily expressed in the proximal tubule, conferred kidney specificity to phosphate-stimulated G-3-P production. Importantly, exogenous G-3-P stimulated FGF23 production when Npt2a or Gpd1 were absent, confirming that it was the key circulating factor downstream of glycolytic phosphate sensing in the kidney. Together, these findings place glycolysis at the nexus of mineral and energy metabolism and identify a kidney-bone feedback loop that controls phosphate homeostasis.
ISSN	00219738
Journal	The Journal of Clinical Investigation
Volume Number	133
PubMed Central reference number	PMC10104895
Issue Number	8
PubMed reference number	36821389
e-ISSN	15588238
DOI	10.1172/JCI164610
Language	English
Publisher	American Society for Clinical Investigation
Publisher Date	2023-04-17
Access Restriction	Open
Rights License	This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. © 2023 Zhou et al.
Subject Keyword	Endocrinology Nephrology Calcium Chronic kidney disease Glucose metabolism
Content Type	Text
Resource Type	Article
Subject	Medicine