Free Deoxycholic Acid Exacerbates Vascular Calcification in CKD through ER Stress-Mediated ATF4 Activation.
Free Deoxycholic Acid Exacerbates Vascular Calcification in CKD through ER Stress-Mediated ATF4 Activation.
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DOI：
10.34067/kid.0007502020
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发表时间：
2021-05
期刊：
影响因子：
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通讯作者：
Miyazaki M
中科院分区：
文献类型：
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作者：
Miyazaki-Anzai S;Masuda M;Shiozaki Y;Keenan AL;Chonchol M;Kremoser C;Miyazaki M
我们的代谢组学方法发现，循环中游离脱氧胆酸（DCA）水平与CKD患者血管钙化的严重程度相关。然而，尚不清楚DCA是否直接导致CKD中的血管钙化。使用各种化学品和动物和细胞培养模型，我们研究了DCA水平的调节是否影响CKD中的血管钙化。CKD通过减少尿DCA排泄增加小鼠和人类中的DCA水平。用DCA但不含其他胆汁酸（BA）处理培养的VSMCs，通过内质网（ER）应激介导的转录激活因子4（ATF 4）激活诱导血管钙化和成骨分化。用法尼醇X受体（FXR）特异性激动剂治疗小鼠，选择性降低循环胆酸衍生的BA（如DCA）水平，保护免受CKD依赖性中膜钙化和动脉粥样硬化钙化。FXR缺乏和DCA治疗通过增加循环DCA水平和激活ER应激反应诱导血管钙化。这项研究表明，DCA通过ER应激介导的ATF4激活在调节CKD依赖性血管疾病中起着致病作用。
Our metabolome approach found that levels of circulating, free deoxycholic acid (DCA) is associated with the severity of vascular calcification in patients with CKD. However, it is not known whether DCA directly causes vascular calcification in CKD. Using various chemicals and animal and cell culture models, we investigated whether the modulation of DCA levels influences vascular calcification in CKD. CKD increased levels of DCA in mice and humans by decreasing urinary DCA excretion. Treatment of cultured VSMCs with DCA but no other bile acids (BAs) induced vascular calcification and osteogenic differentiation through endoplasmic reticulum (ER) stress–mediated activating transcription factor-4 (ATF4) activation. Treatment of mice with Farnesoid X receptor (FXR)–specific agonists selectively reduced levels of circulating cholic acid–derived BAs, such as DCA, protecting from CKD-dependent medial calcification and atherosclerotic calcification. Reciprocal FXR deficiency and DCA treatment induced vascular calcification by increasing levels of circulating DCA and activating the ER stress response. This study demonstrates that DCA plays a causative role in regulating CKD-dependent vascular diseases through ER stress–mediated ATF4 activation.