calcitriol and Vascular-Diseases

Vascular calcification or mineralization is a major complication seen in patients with advanced stages of chronic kidney disease (CKD), and it is associated with markedly increased morbidity and mortality. Most of the CKD-related vascular mineralization is attributable to abnormal mineral ion metabolism. Elevated serum calcium and phosphate levels, along with increased calcium-phosphorus byproduct, and the use of active vitamin D metabolites are thought to be the predisposing factors for developing vascular mineralization in patients with CKD. Recent experimental studies have shown that vascular mineralization can be suppressed by reducing serum phosphate levels, even in the presence of extremely high serum calcium and 1,25-dihydroxyvitamin D levels, indicating that reducing 'phosphate toxicity' should be the important therapeutic priority in CKD patients for minimizing the risk of developing vascular mineralization and the disease progression.

Topics: Animals; Calcinosis; Coronary Disease; Disease Models, Animal; Disease Progression; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glucuronidase; Humans; Hydroxyapatites; Hypercalcemia; Hyperphosphatemia; Klotho Proteins; Mice; Models, Biological; Muscle, Smooth, Vascular; Phosphates; Renal Dialysis; Renal Insufficiency, Chronic; Vascular Diseases; Vitamin D

Chronic kidney disease is associated with an increased risk of cardiovascular disease. Vitamin D deficiency is common in patients with chronic kidney disease. In epidemiological studies, vitamin D deficiency and absence of treatment with vitamin D is associated with increased cardiovascular mortality. Several possible mechanisms may explain how vitamin D can influence the development of cardiovascular disease. Clinical intervention studies are needed to clarify whether treatment with vitamin D decreases the risk of cardiovascular disease in chronic kidney disease.

Topics: Animals; Calcinosis; Cardiovascular Diseases; Heart Failure; Humans; Kidney Failure, Chronic; Renal Dialysis; Risk Factors; Vascular Diseases; Vitamin D; Vitamin D Deficiency

We tested the hypothesis that vascular endothelial function, assessed by endothelium-dependent dilation, is related to serum vitamin D status among middle-aged and older adults without clinical disease, and that this is linked to inflammation. Brachial artery flow-mediated dilation, a measure of endothelium-dependent dilation, was lower (P<0.01) in vitamin D-insufficient (3.7 ± 0.2%; serum 25-hydroxyvitamin D [25(OH)D]: 20 to 29 ng/mL; 62 ± 1 years of age; n = 31; mean± SE) and vitamin D-deficient (3.2 ± 0.3%; 25(OH)D: <20 ng/mL; 63 ± 2 years of age; n = 22) versus vitamin D-sufficient (4.6 ± 0.4%; 25(OH)D: >29 ng/mL; 61 ± 1 years of age; n = 22) subjects, whereas endothelium-independent dilation (brachial dilation to sublingual nitroglycerine) did not differ (P = 0.45). Among all subjects, brachial flow-mediated dilation was positively related to serum 25(OH)D (%Δ: r = 0.35; P<0.01) but not 1,25-dihydroxyvitamin D (r = -0.06; P = 0.61), the active form of vitamin D. Vascular endothelial cell expression of the proinflammatory transcription factor nuclear factor κB was greater in deficient versus sufficient subjects (0.59 ± 0.07 versus 0.44 ± 0.05; P<0.05), and inhibition of nuclear factor κB (4 days oral salsalate) improved flow-mediated dilation to a greater extent in subjects with lower versus higher 25(OH)D (+3.7 ± 0.6 versus +2.0 ± 0.2%; P<0.05). Endothelial cell expression of the downstream proinflammatory cytokine interleukin-6 also was higher in deficient versus sufficient subjects (0.67 ± 0.08 versus 0.47 ± 0.05; P<0.01) and inversely related to serum 25(OH)D level (r = -0.62; P<0.01), whereas vitamin D receptor and 1-α hydroxylase, the 25(OH)D to 1,25-dihydroxyvitamin D converting enzyme, were lower (P<0.05). Inadequate serum 25(OH)D is associated with vascular endothelial dysfunction among healthy middle-aged/older adults, and this is mediated in part by nuclear factor κB-related inflammation. Reduced vitamin D receptor and 1-α hydroxylase may be molecular mechanisms linking vitamin D insufficiency to endothelial dysfunction.

Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Aged; Brachial Artery; Endothelium, Vascular; Female; Humans; Inflammation; Interleukin-6; Male; Middle Aged; NF-kappa B; Nitroglycerin; Receptors, Calcitriol; Salicylates; Vascular Diseases; Vasodilation; Vitamin D; Vitamin D Deficiency

Fibroblastic growth factor 23 (FGF23) regulates renal phosphate reabsorption and 1alpha-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.

Topics: Animals; Calcinosis; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Mice; Mice, Knockout; Phosphorus Metabolism Disorders; Vascular Diseases; Vitamin D