Differential effects of vitamin D analogs on vascular calcification.
We tested the effects of calcitriol and its analog paricalcitol on VSMC calcification in vitro and in vivo. For that reason, cells and animals with five-sixths nephrectomy were treated with both compounds. Calcitriol, but not paricalcitol, increased VSMC calcification in vitro and in vivo independently of calcium and phosphate levels. This increase in calcification was parallel to an increase in the RANKL/OPG ratio.


BACKGROUND
Vascular calcification is a common finding in patients with endstage renal disease. Furthermore, those patients often present secondary hyperparathyroidism, partly because of a decrease of calcitriol synthesis on the kidney. Thus, one of the main therapeutic options is to treat those patients with calcitriol or analogs. However, this treatment presents unwanted side effects, such as increases in vascular calcification.


METHODS
We tested the effect on vascular smooth muscle cell (VSMC) calcification of calcitriol and one of its analogs, paricalcitol, in vitro and in vivo in animals with endstage renal disease.


RESULTS
Calcitriol increased calcification of VSMCs cultured in calcification media. This effect was not present when cells were incubated with paricalcitol. Furthermore, only cells incubated with calcitriol showed an increased RANKL/osteoprotegerin (OPG) expression. Animals with renal failure treated with hypercalcemic doses of calcitriol and paricalcitol showed an increase in systolic blood pressure. However, diastolic blood pressure only raised significantly in those animals treated with paricalcitol. This effect led to a significant increase in pulse pressure in animals treated with calcitriol. The increase in pulse pressure was likely caused by the extensive calcification observed in arteries of animals treated with calcitriol. This increase in calcification was not seen in arteries of animals treated with paricalcitol, despite having similar levels of serum calcium and phosphorus as animals treated with calcitriol. Furthermore, the decreases in serum PTH levels were similar in both treatments.


CONCLUSIONS
We conclude that paricalcitol has a different effect than calcitriol in VSMC calcification and that this could explain part of the differences observed in the clinical settings.
Cardús
Anna
A
Department of Medicine, University of Lleida, Lleida, Spain.
Panizo
Sara
S
Parisi
Eva
E
Fernandez
Elvira
E
Valdivielso
Jose M
JM
D000818:Animals; D001011:Aorta / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D002114:Calcinosis / Q000097:blood* / Q000139:chemically induced / Q000235:genetics; D002117:Calcitriol / Q000494:pharmacology; D002118:Calcium / Q000032:analysis / Q000097:blood / Q000378:metabolism; D002478:Cells, Cultured; D004872:Ergocalciferols / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D009392:Nephrectomy; D053244:Osteoprotegerin / Q000235:genetics; D010281:Parathyroid Hormone / Q000097:blood; D010758:Phosphorus / Q000097:blood; D053245:RANK Ligand / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014652:Vascular Diseases / Q000097:blood* / Q000139:chemically induced / Q000235:genetics; D014807:Vitamin D / Q000031:analogs & derivatives / Q000494:pharmacology*
D050071:Bone Density Conservation Agents; D004872:Ergocalciferols; D053244:Osteoprotegerin; D010281:Parathyroid Hormone; D053245:RANK Ligand; D014807:Vitamin D; D010758:Phosphorus; C084656:paricalcitol; D002117:Calcitriol; D002118:Calcium