Boneexpression and renal regulatory responses to excess phosphate consumption by juvenile swine
Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine
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 bonemRNA expression (250-fold increase relative to LP). Sodium-phosphate co-transporters (and) 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 (and) was unaffected by HP consumption, whereas kidney FGF23 receptors (and) slightly inc
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 bonemRNA expression (250-fold increase relative to LP). Sodium-phosphate co-transporters (and) 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 (and) was unaffected by HP consumption, whereas kidney FGF23 receptors (and) slightly increased. High P intake downregulated renal 1α-hydroxylase () mRNA expression at 108 h, consistent with decreased circulating 1,25(OH)Dconcentrations. In conclusion, HP consumption stimulated boneexpression 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. Graphical Abstract Graphical Abstract Graphical abstract illustrates the physiological consequences in a juvenile pig consuming excess phosphate that leads to hyperphosphatemia. Both PTH and FGF23 hormones are increased and renal phosphate transporters and activation of vitamin D are decreased. These responses act to increase urinary P excretion and restore circulating P to normal ranges. http://www.w3.org/1999/xlink float portrait ziag129ga1.webp float ga1 portrait graphical