Torremadé Noelia, Bozic Milica, Panizo Sara, Barrio-Vazquez Sara, Fernandez-Martín Jose L, Encinas Mario, Goltzman David, Arcidiacono Maria V, Fernandez Elvira, Valdivielso José M
Nephrology Research Department, REDinREN del ISCIII, IRBLleida, University Hospital Arnau de Vilanova, Lleida, Spain.
Bone and Mineral Research Unit, Instituto Reina Sofía de Investigación, REDinREN del ISCIII, Hospital Universitario Central de Asturias, Oviedo, Spain.
J Bone Miner Res. 2016 Oct;31(10):1865-1876. doi: 10.1002/jbmr.2852. Epub 2016 May 4.
Vascular calcification (VC) is a complication of chronic kidney disease that predicts morbidity and mortality. Uremic serum promotes VC, but the mechanism involved is unknown. A role for 1,25(OH) D in VC has been proposed, but the mechanism is unclear because both low and high levels have been shown to increase it. In this work we investigate the role of 1,25(OH) D produced in vascular smooth muscle cells (VSMCs) in VC. Rats with subtotal nephrectomy and kidney recipient patients showed increased arterial expression of 1α-hydroxylase in vivo. VSMCs exposed in vitro to serum obtained from uremic rats also showed increased 1α-hydroxylase expression. Those increases were parallel to an increase in VC. After 6 days with high phosphate media, VSMCs overexpressing 1α-hydroxylase show significantly higher calcium content and RUNX2 expression than control cells. 1α-hydroxylase null mice (KO) with subtotal nephrectomy and treated with calcitriol (400 ng/kg) for 2 weeks showed significantly lower levels of vascular calcium content, Alizarin red staining, and RUNX2 expression than wild-type (WT) littermates. Serum calcium, phosphorus, blood urea nitrogen (BUN), PTH, and 1,25(OH) D levels were similar in both calcitriol-treated groups. In vitro, WT VSMCs treated with uremic serum also showed a significant increase in 1α-hydroxylase expression and higher calcification that was not observed in KO cells. We conclude that local activation of 1α-hydroxylase in the artery mediates VC observed in uremia. © 2016 American Society for Bone and Mineral Research.
血管钙化（VC）是慢性肾脏病的一种并发症，可预测发病率和死亡率。尿毒症血清会促进VC，但其中涉及的机制尚不清楚。有人提出1,25(OH)D在VC中起作用，但其机制尚不清楚，因为已表明低水平和高水平都会增加VC。在这项研究中，我们调查了血管平滑肌细胞（VSMC）中产生的1,25(OH)D在VC中的作用。行次全肾切除术的大鼠和肾移植受者体内动脉1α-羟化酶的表达增加。体外暴露于尿毒症大鼠血清的VSMC也显示1α-羟化酶表达增加。这些增加与VC的增加平行。在高磷培养基中培养6天后，过表达1α-羟化酶的VSMC显示钙含量和RUNX2表达明显高于对照细胞。行次全肾切除术并用骨化三醇（400 ng/kg）治疗2周的1α-羟化酶基因敲除小鼠（KO），其血管钙含量、茜素红染色和RUNX2表达水平明显低于野生型（WT）同窝小鼠。两个骨化三醇治疗组的血清钙、磷、血尿素氮（BUN）、甲状旁腺激素（PTH）和1,25(OH)D水平相似。在体外，用尿毒症血清处理的WT VSMC也显示1α-羟化酶表达显著增加，钙化程度更高，而在KO细胞中未观察到这种情况。我们得出结论，动脉中1α-羟化酶的局部激活介导了尿毒症中观察到的VC。©2016美国骨与矿物质研究学会。
