Role of phosphorus and vitamin D analogs in the pathogenesis of vascular calcification

Vascular calcification is a mortality risk factor for stage 5 chronic kidney disease patients. We investigated the role of phosphorus and vitamin D analogs in the pathogenesis of vascular calcification using in vivo, ex vivo, and in vitro models. Our results demonstrate that uremic rats receiving a hyperphosphatemia-inducing diet did not exhibit aortic calcification despite elevated levels of serum phosphorus and calcium-phosphorus (CaxP) product. The vitamin D analog 1 alpha-hydroxyvitamin-D-2 [1 alpha(OH)D-2] at 0.17 mu g/kg raised serum calcium, phosphorus, CaxP product, and aortic calcification in the uremic rats, but 19-nor-1 alpha, 25(OH)(2)D-2 (19-nor) at the same dose had no significant effect. At 0.67 mu g/kg, both 1 alpha(OH)D-2 and 19-nor had similar effects on serum calcium, phosphorus, and CaxP product, but only 1 alpha(OH)D-2 induced significant aortic calcification. Only aortic rings from 1 alpha(OH)D-2-treated uremic rats exhibited a significant increase in Ca-45 uptake ex vivo. When aortic rings from normal rats or a primary culture of human coronary artery smooth muscle cells were treated with phosphorus or vitamin D analogs in vitro, high phosphorus induced calcium accumulation and/or Ca-45 uptake in a dose- or time-dependent manner, whereas vitamin D analogs including 1 alpha(OH) D-2 up to 100 nM had no significant effect despite the presence of a functional vitamin D receptor. However, serum from 1 alpha(OH)D-2-treated uremic rats induced Ca-45 uptake into smooth muscle cells cultured in high phosphorus. These results suggest that the regulation of vascular calcification in vivo cannot be easily replicated in the ex vivo or in vitro models, and high phosphorus and some vitamin D analogs such as 1 alpha(OH)D-2 exert interactive effects on modulating vascular calcification.