vitamin-d-2 and Aortic-Diseases

Vascular calcification is common in chronic kidney disease, where cardiovascular mortality remains the leading cause of death. Patients with kidney disease are often prescribed vitamin D receptor agonists (VDRAs) that confer a survival benefit, but the underlying mechanisms remain unclear. Here we tested two VDRAs in a mouse chronic kidney disease model where dietary phosphate loading induced aortic medial calcification. Mice were given intraperitoneal calcitriol or paricalcitol three times per week for 3 weeks. These treatments were associated with half of the aortic calcification compared to no therapy, and there was no difference between the two agents. In the setting of a high-phosphate diet, serum parathyroid hormone and calcium levels were not significantly altered by treatment. VDRA therapy was associated with increased serum and urine klotho levels, increased phosphaturia, correction of hyperphosphatemia, and lowering of serum fibroblast growth factor-23. There was no effect on elastin remodeling or inflammation; however, the expression of the anticalcification factor, osteopontin, in aortic medial cells was increased. Paricalcitol upregulated osteopontin secretion from mouse vascular smooth muscle cells in culture. Thus, klotho and osteopontin were upregulated by VDRA therapy in chronic kidney disease, independent of changes in serum parathyroid hormone and calcium.

Topics: Animals; Aorta; Aortic Diseases; Calcitriol; Calcium; Cells, Cultured; Diet; Disease Models, Animal; Elastin; Ergocalciferols; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glucuronidase; Injections, Intraperitoneal; Klotho Proteins; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Osteopontin; Parathyroid Hormone; Phosphates; Receptors, Calcitriol; Renal Insufficiency, Chronic; Time Factors; Up-Regulation; Vascular Calcification

Chronic kidney disease (CKD) is characterized by accelerated vascular calcification, which may in part be caused by deficiency of the anti-aging factor Klotho. Lau et al. demonstrate that administration of active vitamin D and its analog decreases aortic calcification in association with increases in two potent calcification inhibitors--the secreted form of Klotho and vascular osteopontin. These data might provide a new perspective on the association of active vitamin D with improved survival in patients with CKD.

Topics: Animals; Aorta; Aortic Diseases; Calcitriol; Diet; Ergocalciferols; Female; Glucuronidase; Klotho Proteins; Osteopontin; Phosphates; Receptors, Calcitriol; Renal Insufficiency, Chronic; Vascular Calcification

An apparent conflict exists between observational studies that suggest that vitamin D receptor (VDR) activators provide a survival advantage for patients with ESRD and other studies that suggest that they cause vascular calcification. In an effort to explain this discrepancy, we studied the effects of the VDR activators calcitriol and paricalcitol on aortic calcification in a mouse model of chronic kidney disease (CKD)-stimulated atherosclerotic cardiovascular mineralization. At dosages sufficient to correct secondary hyperparathyroidism, calcitriol and paricalcitol were protective against aortic calcification, but higher dosages stimulated aortic calcification. At protective dosages, the VDR activators reduced osteoblastic gene expression in the aorta, which is normally increased in CKD, perhaps explaining this inhibition of aortic calcification. Interpreting the results obtained using this model, however, is complicated by the adynamic bone disorder; both calcitriol and paricalcitol stimulated osteoblast surfaces and rates of bone formation. Therefore, the skeletal actions of the VDR activators may have contributed to their protection against aortic calcification. We conclude that low, clinically relevant dosages of calcitriol and paricalcitol may protect against CKD-stimulated vascular calcification.

Topics: Animals; Aorta; Aortic Diseases; Bone Density Conservation Agents; Bone Diseases, Endocrine; Calcinosis; Calcitriol; Calcium; Dietary Fats; Ergocalciferols; Female; Femur; Gene Expression; Kidney Failure, Chronic; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Osteoblasts; Phosphorus; Receptors, Calcitriol

Vascular calcification is associated with cardiovascular disease, the most common cause of death in chronic kidney disease (CKD). Patients with CKD are treated with vitamin D receptor activators (VDRAs); therefore, we determined if this treatment affects vascular calcification. Uremic rats were given vehicle, calcitriol, paricalcitol, or doxercalciferol three times a week for 1 month. Calcitriol significantly increased the serum calcium-phosphate product and aortic calcium content. Paricalcitol had no effect but the same dose of doxercalciferol significantly increased the calcium-phosphate product and the aortic calcium content, the latter being confirmed by von Kossa staining. To see if the increased aortic calcium was due to an increased serum calcium-phosphate product or to a differential effect of the two VDRAs, we lowered the dose of doxercalciferol and increased the dose of paricalcitol. A lower doxercalciferol did not increase the calcium-phosphate product but increased the aortic calcium content. A higher dose of paricalcitol still had no effect. Doxercalciferol treatment increased the mRNA and protein expression of the bone-related markers Runx2 and osteocalcin in the aorta, whereas paricalcitol did not. Hence, different VDRAs have different effects on vascular calcification in uremic rats. The effects are independent of the serum calcium-phosphate product suggesting independent mechanisms.

Topics: Animals; Aorta; Aortic Diseases; Bone Density Conservation Agents; Calcinosis; Calcitriol; Calcium; Ergocalciferols; Female; Parathyroid Hormone; Phosphates; Rats; Rats, Sprague-Dawley; Receptors, Calcitriol; Uremia

The present study was undertaken to examine changes in vascular ultrastructure of rats subjected to hypervitaminosis D with or without treatment with ethane-I-hydroxy-I, I-diphosphonate (EHDP). Five groups of rats were studied. Untreated rats were given 0.9% NaCl i.p. Sham-treated rats were given vehicle (corn oil). Treated rats were given ergocalciferol (75,000 IU i.p.) dissolved in vehicle with or without EHDP (5 mM/100 g body-weight i.p.). Rats which had been given ergocalciferol without EHDP developed hypercalcemia and demonstrated significant arterial calcinosis. A similar degree of calcinosis was not observed in rats given ergocalciferol with EHDP. EHDP appeared to inhibit arterial calcinosis; however, it did not affect plasma calcium levels. This suggests that EHDP might delay calcium influx into the cell and thereby prevent calcium overload. Our findings support the suggestion that EHDP therapy can be an effective treatment for the inhibition of dystrophic arterial calcinosis.

Topics: Animals; Aorta, Thoracic; Aortic Diseases; Calcinosis; Ergocalciferols; Etidronic Acid; Male; Microscopy, Electron; Rats; Rats, Inbred Strains

Topics: Animals; Aorta; Aortic Diseases; Arteriosclerosis; Cholesterol; Ergocalciferols; Male; Microscopy, Electron; Rats; Rats, Inbred Strains

Topics: Animals; Animals, Newborn; Aortic Diseases; Calcinosis; Calcium; Cholesterol; Dose-Response Relationship, Drug; Ergocalciferols; Female; Fetal Death; Hydroxycholecalciferols; Magnesium; Phosphorus; Pregnancy; Rabbits

Topics: Adenosine Triphosphatases; Animals; Aorta; Aortic Diseases; Arteriosclerosis; Ergocalciferols; Esterases; Freund's Adjuvant; Glutamate Dehydrogenase; L-Lactate Dehydrogenase; Monoamine Oxidase; Necrosis; Rabbits; Succinate Dehydrogenase

Topics: Animals; Aorta; Aortic Diseases; Arteriosclerosis; Cholesterol; Coronary Disease; Coronary Vessels; Diet, Atherogenic; Ergocalciferols; Male; Rats

Topics: Animals; Aorta; Aortic Diseases; Ergocalciferols; Female; Glycosaminoglycans; Hydroxyproline; Male; Minerals; Rabbits; Sex Factors; Vascular Diseases

Topics: Animals; Aortic Diseases; Calcinosis; Ergocalciferols; Phosphates; Polymers; Rats; Staining and Labeling

Topics: Aorta; Aortic Diseases; Child; Coronary Disease; Coronary Vessels; Drug Therapy; Ergocalciferols; Histocytochemistry; Humans; Infant; Lipidoses; Pathology; Rickets; USSR