Effect of paricalcitol and calcitriol on aortic wall remodeling in uninephrectomized ApoE knockout mice

Abstract

Despite an only minor reduction in the glomerular filtration rate, uninephrectomy (UNX) markedly accelerates the rate of growth of atherosclerotic plaques in ApoE-/- mice. It has been suggested that vitamin D receptor (VDR) activation exerts an antiproliferative effect on vascular smooth muscle cells, but the side effects may limit its use. To assess a potentially different spectrum of actions, we compared the effects of paricalcitol and calcitriol on remodeling and calcification of the aortic wall in sham-operated and UNX ApoE-/- mice on a diet with normal cholesterol content. Sham-operated and UNX mice were randomly allotted to treatment with solvent, calcitriol (0.03 μg/kg) or paricalcitol (0.1 μg/kg) 5 times/wk intraperitoneally for 10 wk. Semithin (0.6 μm) sections of the aorta were analyzed by 1) morphometry, 2) immunohistochemistry, and 3) Western blotting of key proteins involved in vascular calcification and growth. Compared with sham-operated animals (5.6 ± 0.24), the wall-to-lumen ratio (x100) of the aorta was significantly higher in solvent- and calcitriol-treated UNX animals (6.64 ± 0.27 and 7.17 ± 0.81, respectively, P < 0.05), but not in paricalcitol-treated UNX (6.1 5 ± 0.32). Similar differences were seen with respect to maximal plaque height. Expression of transforming growth factor (TGF)-β1 in aortic intima/plaque was also significantly higher in UNX solvent and UNX calcitriol compared with sham-operated and UNX paricalcitol animals. Treatment with both paricalcitol and calcitriol caused significant elevation of VDR expression in the aorta. While at the dose employed paricalcitol significantly reduced TGF-β expression in plaques, calcitriol in contrast caused significant vascular calcification and elevated expression of related proteins (BMP2, RANKL, and Runx2).

The calcimimetic R-568 prevents podocyte loss in uninephrectomized ApoE−/−mice

“…The serum ionized Ca 2ϩ concentration was not different between the groups when measured 24 h postdosing as the decrease of serum Ca 2ϩ after the administration of R-568 is known to be transient (5). At the dose used, calcitriol did not cause hypercalcemia, in agreement with previous experiments (2).…”

Mechanistic Insights into Vascular Calcification in CKD

“…74 However, other studies show that vitamin D has protective effects by increasing calcification inhibitory proteins such as MGP and osteopontin, 75 reducing proinflammatory cytokines, such as IL-6, IL-1b, and TGF-b. 76 Importantly, FGF-23 can downregulate the renal 1-ahydroxylase receptor, thereby reducing vitamin D production, 77 suggesting a complex interplay between FGF-23-Klotho and vitamin D on the vasculature. The proposed mechanisms of VDRA action on the VSMC are shown in Figure 3.…”

“…78 In addition, differential effects on vascular calcification have been demonstrated between different VDRAs that are independent of calcium and phosphate effects; doxercalciferol, a D2 analog, was shown to induce the expression of Runx2 and osteocalcin, 79 whereas paricalcitol did not induce these effects or cause osteoblastic differentiation. 76,79 Moreover, clinical and in vitro studies suggest that there may in fact be a bimodal association of vitamin D levels with vascular measures such that both low and high levels of vitamin D associate with abnormal vascular effects. 80,81 Further studies are required to determine the optimal VDRA and its optimal dose for vascular health.…”

25-Hydroxyvitamin D31-Alpha-Hydroxylase-Dependent Stimulation of Renal Klotho Expression by Spironolactone

“…Despite the stimulatory effect of 1,25(OH) 2 D 3 on phosphate reabsorption, reduced levels of 1,25(OH) 2 D 3 are similarly associated with increased mortality in CKD patients [54]. Although previous studies in preclinical models suggested an adverse effect of calcitriol on vascular calcification, supplementation of 1,25(OH) 2 D 3 at physiological doses increased klotho levels and provided beneficial effects [57,58,59]. Moreover, 1,25(OH) 2 D 3 stimulates nitric oxide production [60] and modifies glucose metabolism.…”