Bone FGF23 expression and renal regulatory responses to excess phosphate consumption by juvenile swine
TL;DR
Roles of FGF23 in P homeostasis in a large animal, healthy swine model were validated, with HP consumption stimulated bone FGF23 expression and renal adaptive responses in healthy pigs, consistent with roles of FGF23-mediated phosphaturia and regulation of vitamin D metabolism for maintenance of P homeostasis.
Abstract
Abstract Fibroblast growth factor 23 (FGF23), a bone-derived hormone, regulates phosphorus (P) homeostasis by modulation of renal P excretion and vitamin D metabolism. Physiological roles of FGF23 have been mainly characterized in human disorders of P metabolism and murine models. This study aimed to validate roles of FGF23 in P homeostasis in a large animal, healthy swine model. Juvenile pigs fed a low-P diet (LP) for 4 d were fasted overnight then fed a high-P diet (HP) for 5 d. Blood was collected to determine plasma concentrations of P, calcium (Ca), PTH, and vitamin D metabolites, and urine was collected to assess P and Ca concentrations. Femur and kidney tissues were collected to assess gene and protein expression related to FGF23 synthesis, signaling, and vitamin D metabolism. The rapid increase in plasma P (5 to 18 mg/dL) within 12 h of HP intake was lagged by increased urinary P. At maximal urinary P concentration (108 h), plasma P had returned to physiological ranges. The initial increase in plasma PTH with HP intake returned to baseline levels by 108 h. At 108 h, HP consumption upregulated bone FGF23 mRNA expression (250-fold increase relative to LP). Sodium-phosphate co-transporters (NaPi2a and NaPi2c) mRNA and NaPi2a protein expression decreased with HP intake, consistent with FGF23-mediated phosphaturia, independent of circulating PTH. Bone mRNA expression of post-translational FGF23 regulators (GALNT3 and FURIN) was unaffected by HP consumption, whereas kidney FGF23 receptors (FGFR1 and αKLOTHO) slightly increased. High P intake downregulated renal 1α-hydroxylase (CYP27B1) mRNA expression at 108 h, consistent with decreased circulating 1,25(OH)2D3 concentrations. In conclusion, HP consumption stimulated bone FGF23 expression and renal adaptive responses in healthy pigs, consistent with roles of FGF23-mediated phosphaturia and regulation of vitamin D metabolism for maintenance of P homeostasis, as previously described in humans and rodents.
