Kidney360. 2021 May;2(5):857-868. doi: 10.34067/kid.0007502020. Epub 2021 May 27.

Free Deoxycholic Acid Exacerbates Vascular Calcification in CKD through ER Stress-Mediated ATF4 Activation.

Kidney360

Shinobu Miyazaki-Anzai, Masashi Masuda, Yuji Shiozaki, Audrey L Keenan, Michel Chonchol, Claus Kremoser, Makoto Miyazaki

PMID: 34423309 PMCID: PMC8378801 DOI: 10.34067/kid.0007502020

Abstract

BACKGROUND: 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.

METHODS: Using various chemicals and animal and cell culture models, we investigated whether the modulation of DCA levels influences vascular calcification in CKD.

RESULTS: 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.

CONCLUSIONS: This study demonstrates that DCA plays a causative role in regulating CKD-dependent vascular diseases through ER stress-mediated ATF4 activation.

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Publication Types

• Journal Article

Grant support

• R01 HL133545/HL/NHLBI NIH HHS/United States
• R01 HL117062/HL/NHLBI NIH HHS/United States
• R01 HL132318/HL/NHLBI NIH HHS/United States
• R01 DK124901/DK/NIDDK NIH HHS/United States
• R01 DK096030/DK/NIDDK NIH HHS/United States