Role of Hyperphosphatemia and 1,25-Dihydroxyvitamin D in Vascular Calcification and Mortality in Fibroblastic Growth Factor 23 Null Mice

Abstract

Fibroblastic growth factor 23 (FGF23) regulates renal phosphate reabsorption and 1␣-hydroxylase activity. Ablation of FGF23 results in elevated serum phosphate, calcium, and 1,25-dihydroxyvitamin D3 [1,25(OH) 2 D] levels; vascular calcifications; and early death. For determination of the independent roles of hyperphosphatemia and excess vitamin D activity on the observed phenotypic abnormalities, FGF23 null mice were fed a phosphate-or vitamin D-deficient diet. The phosphate-deficient diet corrected the hyperphosphatemia, prevented vascular calcifications, and rescued the lethal phenotype in FGF23 null mice, despite persistent elevations of serum 1,25(OH) 2 D and calcium levels. This suggests that hyperphosphatemia, rather than excessive vitamin D activity, is the major stimulus for vascular calcifications and contributes to the increased mortality in the FGF23-null mouse model. In contrast, the vitamin D-deficient diet failed to correct either the hyperphosphatemia or the vascular calcifications in FGF23 null mice, indicating that FGF23 independently regulates renal phosphate excretion and that elevations in 1,25(OH) 2 D and calcium are not sufficient to induce vascular calcifications in the absence of hyperphosphatemia. The vitamin D-deficient diet also improved survival in FGF23 null mice in association with normalization of 1,25(OH) 2 D and calcium levels and despite persistent hyperphosphatemia and vascular calcifications, indicating that excessive vitamin D activity can also have adverse effects in the presence of hyperphosphatemia and absence of FGF23. Understanding the independent and context-dependent interactions between hyperphosphatemia and excessive vitamin D activity, as well as vascular calcifications and mortality in FGF23 null mice, may ultimately provide important insights into the management of clinical disorders of hyperphosphatemia and excess vitamin D activity. 18: 211618: -212418: , 200718: . doi: 10.1681 Disorders of mineral metabolism are nontraditional risk factors that are associated with high mortality in ESRD. 1,2 Epidemiologic studies have linked excessive cardiovascular mortality in ESRD with hyperphosphatemia, hypercalcemia, and elevated parathyroid hormone (PTH) levels. 2,3 Vascular calcifications, which are highly prevalent and directly correlated with mortality in this population, are the likely mechanism whereby disordered mineral metabolism contributes to cardiovascular mortality in ESRD. 3 Experimental models demonstrate that hyperphosphatemia is a major initiator of extracellular matrix mineralization and vascular calcification. 4 In addition, clinical data in ESRD show a strong association between hyperphosphatemia and mortality, as well as between phosphate levels and excess calcium with vascular calcifications. 2,5,6 The relationship among disordered mineral metabolism, the presence of vascular calcifications, and J Am Soc Nephrol

Longitudinal Relationships among Coronary Artery Calcification, Serum Phosphorus, and Kidney Function

“…Experimental models in both uremic and nonuremic animals support hyperphosphatemia as central to the process of vascular calcification. Irrespective of kidney function, mice or rats with higher serum phosphorus develop prominent aortic calcification that can be corrected by phosphate-binding drugs or dietary restriction (7)(8)(9)(10)20). A growing series of observations in humans are consistent with experimental models in that higher serum phosphorus has been reported to predict CAC and CVD events in people without clinically apparent kidney disease (11)(12)(13).…”

Evaluation of a Method for Fibroblast Growth Factor-23: A Novel Biomarker of Adverse Outcomes in Patients with Renal Disease

“…7 It will be of considerable interest to look at FGF-23 levels and their prognostic value because patients with metabolic syndrome have evidence of incipient renal disease manifesting as microalbuminuria. Commercially available assays for both intact FGF-23 and the splice product carboxyterminal FGF-23 are now available.…”

“…[1][2][3][4][5] 2 D levels, and they die prematurely. 7 In long-term hemodialysis patients, high levels of carboxy-terminal FGF-23 were significantly associated with the 2-year mortality rate, with a significantly increased hazard ratio (HR) of 2.5. 8 Also, Gutierrez et al 9 demonstrated in a prospective cohort of 10,044 patients with chronic kidney disease that median carboxy-terminal FGF-23 levels were significantly higher compared to controls.…”

Klotho Up-regulates Renal Calcium Channel Transient Receptor Potential Vanilloid 5 (TRPV5) by Intra- and Extracellular N-glycosylation-dependent Mechanisms

“…Mice with homozygous knockout of fgf23 have profound hyperphosphatemia and the same premature aging phenotypes as homozygous kl hypomorphic mice (23). Dietary phosphate restriction rescues premature aging and death in both fgf23 knockout and kl hypomorphic mice (24,25).…”