FGF23 regulates phosphate and vitamin D metabolism during acute kidney injury and recovery.

Acute kidney injury (AKI) triggers a rapid rise in circulating fibroblast growth factor 23 (FGF23), potentially mediated by elevations in glycerol-3-phosphate (G-3-P). Although elevated FGF23 contributes to mineral and bone disorder in chronic kidney disease (CKD), its pathophysiological role and temporal changes in mineral metabolism during AKI and recovery remain incompletely understood. We investigated longitudinal changes in mineral metabolism, including FGF23 and G-3-P, in a rat ischemia-reperfusion injury (IRI) model induced by unilateral nephrectomy followed by 35 min of contralateral IRI, and evaluated the effects of a pan-fibroblast growth factor receptor (FGFR) inhibitor (PD173074). IRI induced acute hyperphosphatemia with rapid increases in FGF23 and G-3-P, accompanied by increased urinary phosphate excretion, reduced 1,25-dihydroxyvitamin D, and elevated parathyroid hormone levels in the early phase. During recovery, FGF23 and G-3-P levels declined in parallel with improvement in hyperphosphatemia, followed by restoration of 1,25-dihydroxyvitamin D synthesis. Pharmacological inhibition of FGFR signaling resulted in persistent hyperphosphatemia while attenuating the decline in 1,25-dihydroxyvitamin D. These findings demonstrate that FGF23 and mineral metabolism undergo rapid and reversible alterations following AKI. The acute rise in FGF23 appears to represent an adaptive response to limit hyperphosphatemia at the expense of reduced 1,25-dihydroxyvitamin D and secondary hyperparathyroidism, resembling CKD but with faster onset and reversibility during recovery.NEW & NOTEWORTHY Acute kidney injury (AKI) induces a rapid increase in fibroblast growth factor 23 (FGF23). We show that the acute rise in FGF23 functions as an adaptive response to promote phosphaturia and mitigate hyperphosphatemia, at the cost of reduced 1,25-dihydroxyvitamin D and secondary hyperparathyroidism. Pharmacological FGFR inhibition disrupts this response, leading to sustained hyperphosphatemia. These findings identify FGF23 as a key early regulator of mineral homeostasis during AKI and recovery.