Differential effects of vitamin D receptor activators on vascular calcification in uremic rats

Abstract

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.

Vitamin D Receptor Activators Can Protect against Vascular Calcification

“…10,12,15 The actions of the VDR activators on aortic calcification reported here are not in disagreement with these reports, because when we used a dosage of paricalcitol (paricalcitol 400 ng/kg) equivalent to the VDR activator dosages used in the previous reports; we also observed stimulation of aortic Ca content (Figure 1). The stimulation of vascular Ca content in the group that was treated with 400 ng/kg paricalcitol was due to increased deposition of vascular Ca in the atherosclerotic plaque.…”

Vitamin D Attenuates Endothelial Dysfunction in Uremic Rats and Maintains Human Endothelial Stability

“…Moreover, while in vitro studies suggested a protective role for vitamin D in ameliorating damaged endothelium,12, 13 experimental in vivo CKD studies have primarily focused on the prevention of vascular calcification of the medial layer and heart failure9, 14, 15 but paid little attention to structural endothelial damage. A small number of prior studies have suggested benefits of the active vitamin D analogue paricalcitol on endothelial stability in animal models of CKD16, 17 and even in patients 18, 19.…”

Bone and Mineral Guidelines for Patients with Chronic Kidney Disease

“…The choice of which VDRA to use should be based on clinically exposed differences in efficacy and safety. New preclinical studies indicate that calcitriol and doxercalciferol but not paricalcitol stimulate aortic expression of cbfa1/runx2 and osteocalcin, in addition to promoting marked aortic calcium accumulation (27). This suggests a potential protective effect for paricalcitol for not stimulating aortic vascular smooth muscle cells to undergo a transition to the osteoblast phenotype under conditions of hyperphosphatemia (28).…”