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血管紧张素原在磷酸盐诱导的血管平滑肌细胞成骨样转化中的作用。

Involvement Of Vascular Aldosterone Synthase In Phosphate-Induced Osteogenic Transformation Of Vascular Smooth Muscle Cells.

机构信息

Department of Physiology, University of Tübingen, Tübingen, Germany.

Department of Internal Medicine and Cardiology, Charité University Medicine, Campus Virchow-Klinikum, Berlin, Germany.

出版信息

Sci Rep. 2017 May 17;7(1):2059. doi: 10.1038/s41598-017-01882-2.

DOI:10.1038/s41598-017-01882-2
PMID:28515448
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5435689/
Abstract

Vascular calcification resulting from hyperphosphatemia is a major determinant of mortality in chronic kidney disease (CKD). Vascular calcification is driven by aldosterone-sensitive osteogenic transformation of vascular smooth muscle cells (VSMCs). We show that even in absence of exogenous aldosterone, silencing and pharmacological inhibition (spironolactone, eplerenone) of the mineralocorticoid receptor (MR) ameliorated phosphate-induced osteo-/chondrogenic transformation of primary human aortic smooth muscle cells (HAoSMCs). High phosphate concentrations up-regulated aldosterone synthase (CYP11B2) expression in HAoSMCs. Silencing and deficiency of CYP11B2 in VSMCs ameliorated phosphate-induced osteogenic reprogramming and calcification. Phosphate treatment was followed by nuclear export of APEX1, a CYP11B2 transcriptional repressor. APEX1 silencing up-regulated CYP11B2 expression and stimulated osteo-/chondrogenic transformation. APEX1 overexpression blunted the phosphate-induced osteo-/chondrogenic transformation and calcification of HAoSMCs. Cyp11b2 expression was higher in aortic tissue of hyperphosphatemic klotho-hypomorphic (kl/kl) mice than in wild-type mice. In adrenalectomized kl/kl mice, spironolactone treatment still significantly ameliorated aortic osteoinductive reprogramming. Our findings suggest that VSMCs express aldosterone synthase, which is up-regulated by phosphate-induced disruption of APEX1-dependent gene suppression. Vascular CYP11B2 may contribute to stimulation of VSMCs osteo-/chondrogenic transformation during hyperphosphatemia.

摘要

高磷血症引起的血管钙化是慢性肾脏病（CKD）患者死亡的主要决定因素。血管钙化是由血管平滑肌细胞（VSMC）的醛固酮敏感成骨转化驱动的。我们发现，即使没有外源性醛固酮，沉默和药理学抑制（螺内酯、依普利酮）矿皮质激素受体（MR）也能改善磷酸盐诱导的原代人主动脉平滑肌细胞（HAoSMCs）的成骨/软骨转化。高磷浓度上调 HAoSMCs 中的醛固酮合酶（CYP11B2）表达。沉默和 VSMC 中 CYP11B2 的缺乏改善了磷酸盐诱导的成骨重编程和钙化。磷酸盐处理后，APEX1 被核输出，APEX1 是 CYP11B2 的转录抑制剂。APEX1 沉默上调 CYP11B2 表达并刺激成骨/软骨转化。APEX1 过表达减弱了磷酸盐诱导的 HAoSMCs 的成骨/软骨转化和钙化。klotho 低表达（kl/kl）小鼠的主动脉组织中 Cyp11b2 的表达高于野生型小鼠。在肾上腺切除术的 kl/kl 小鼠中，螺内酯治疗仍能显著改善主动脉成骨诱导重编程。我们的研究结果表明，VSMC 表达醛固酮合酶，其被磷酸盐诱导的 APEX1 依赖性基因抑制破坏所上调。血管 CYP11B2 可能有助于在高磷血症期间刺激 VSMC 的成骨/软骨转化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1ba/5435689/a10a08fe1abe/41598_2017_1882_Fig8_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1ba/5435689/a10a08fe1abe/41598_2017_1882_Fig8_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1ba/5435689/ba310417a6df/41598_2017_1882_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1ba/5435689/2fb183438bc0/41598_2017_1882_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1ba/5435689/7658562f7804/41598_2017_1882_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1ba/5435689/705d149f2041/41598_2017_1882_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1ba/5435689/a10a08fe1abe/41598_2017_1882_Fig8_HTML.jpg

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