Impaired arterial vitamin D signaling occurs in the development of vascular calcification.
Impaired arterial vitamin D signaling occurs in the development of vascular calcification.
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DOI：
10.1371/journal.pone.0241976
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发表时间：
2020
期刊：
影响因子：
3.7
通讯作者：
Zehnder D
中科院分区：
文献类型：
--
作者：
Lim K;Molostvov G;Lubczanska M;Fletcher S;Bland R;Hiemstra TF;Zehnder D
关于维生素 D 受体激动剂 (VDRa) 是否能保护动脉钙化，存在相互矛盾的数据。令人困惑的是，人类和动物实验模型之间固有的生理差异，以及我们目前对动脉维生素 D 代谢、疾病状态的变化以及对 VDRa 的反应的支离破碎的理解。在此，该研究旨在通过利用人体动脉器官培养模型的前沿来解决这些问题。人类动脉采集自总共 24 名患者（健康对照，n = 12；终末期 CKD，n = 12）。使用离体正常和钙化（含5mmol/L CaCl2和5mmol/L β-甘油磷酸）培养基处理的动脉器官培养物进行横断面和介入研究。为了评估 VDRa 治疗的作用，用骨化三醇或帕立骨化醇治疗动脉。我们发现人类动脉表达功能活跃的维生素 D 系统，包括 VDR、1α-羟化酶和 24-羟化酶 (24-OHase) 成分，这些成分在 CKD 动脉中失调。 VDRa 治疗增加了健康动脉中的 VDR 表达 (p<0.01)，但在 CKD 动脉中没有增加。 VDRa 治疗对健康动脉和 CKD 动脉中的动脉 1α-OHase (p<0.05) 和 24-OHase mRNA 和蛋白表达进行了差异调节。 VDRa 暴露抑制了 CKD 动脉中 Runx2 和 MMP-9 的表达，但只有帕立骨化醇抑制了 MMP-2。 VDRa 暴露并未调节所有器官培养模型中的动脉钙化。然而，在体外钙化条件下，VDRa 降低了人主动脉平滑肌细胞中衰老相关 β-半乳糖苷酶 (SAβG) 染色的表达。总之，CKD 中会发生动脉维生素 D 信号成分的适应不良。 VDRa 暴露可以发挥血管保护作用，似乎对于 CKD 患者动脉健康的调节至关重要。
Conflicting data exists as to whether vitamin D receptor agonists (VDRa) are protective of arterial calcification. Confounding this, is the inherent physiological differences between human and animal experimental models and our current fragmented understanding of arterial vitamin D metabolism, their alterations in disease states and responses to VDRa’s. Herein, the study aims to address these problems by leveraging frontiers in human arterial organ culture models. Human arteries were collected from a total of 24 patients (healthy controls, n = 12; end-stage CKD, n = 12). Cross-sectional and interventional studies were performed using arterial organ cultures treated with normal and calcifying (containing 5mmol/L CaCl2 and 5mmol/L β-glycerophosphate) medium, ex vivo. To assess the role of VDRa therapy, arteries were treated with either calcitriol or paricalcitol. We found that human arteries express a functionally active vitamin D system, including the VDR, 1α-hydroxylase and 24-hydroxylase (24-OHase) components and these were dysregulated in CKD arteries. VDRa therapy increased VDR expression in healthy arteries (p<0.01) but not in CKD arteries. Arterial 1α-OHase (p<0.05) and 24-OHase mRNA and protein expression were modulated differentially in healthy and CKD arteries by VDRa therapy. VDRa exposure suppressed Runx2 and MMP-9 expression in CKD arteries, however only paricalcitol suppressed MMP-2. VDRa exposure did not modulate arterial calcification in all organ culture models. However, VDRa reduced expression of senescence associated β-galactosidase (SAβG) staining in human aortic-smooth muscle cells under calcifying conditions, in vitro. In conclusion, maladaptation of arterial vitamin D signaling components occurs in CKD. VDRa exposure can exert vasculo-protective effects and seems critical for the regulation of arterial health in CKD.
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影响因子：
3.7
作者：
Schmidt N;Brandsch C;Kühne H;Thiele A;Hirche F;Stangl GI
通讯作者：
Stangl GI
影响因子：
2.1
作者：
Luo, XH;Liao, EY
通讯作者：
Liao, EY
影响因子：
13.6
作者：
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通讯作者：
Chen, Neal X.
DOI：
10.2215/cjn.00900208
发表时间：
2008-11-01
影响因子：
9.8
作者：
Andrade, Jason;Er, Lee;Levin, Adeera
通讯作者：
Levin, Adeera
影响因子：
13.6
作者：
Finch, JL;Dusso, AS;Slatopolsky, EA
通讯作者：
Slatopolsky, EA