Abstract 14937: Deoxycholic Acid Contributes to Chronic Kidney Disease-Dependent Vascular Calcification
Cardiovascular disease (CVD) is the major cause of mortality in individuals with chronic kidney disease (CKD).
CKD patients have more than a 20-fold higher risk of developing CVD. More than 80% of men and 50% of women with CKD develop vascular calcification, leading to death. However, the cellular and molecular mechanisms by which CKD accelerates cardiovascular disease are still poorly understood. Our previous study showed that FXR activation inhibited vascular calcification in tissue culture and in animal models using ApoE knockout (KO) mice with 5/6 nephrectomy (nx). In this study, we examined the molecular mechanism by which FXR activation attenuated CKD-dependent vascular calcification. We found that CKD increased levels of circulating bile acids such as cholic acid (CA) and chenodeoxycholic acid (CDCA). FXR agonists (INT-747 and Px20606) significantly reduced hepatic CYP8B1 expression, resulting in the specific reduction of CA metabolites such as deoxycholic acid (DCA). In contrast to FXR activation, FXR deficiency accelerated vascular calcification in both ApoE KO mice and LDLR KO mice with 5/6 nx, and also increased circulating bile acids such as DCA. In addition, DCA but not other major bile acids induced the PERK-eIF2α-ATF4-CHOP signaling of the ER stress in vascular smooth muscle cells, resulting in vascular calcification. CHOP and ATF4 knockdown attenuated DCA-induced vascular calcification. These results demonstrate that increased DCA contributes to CKD-dependent vascular calcification.
This work was supported by grants from NIH (R01DK096030-01A1 and R01HL117062-01A1), AHA (12BGIA11380005, 10BGIA4580053 and 13POST13820008) and Phenex Pharmaceuticals.
- © 2013 by American Heart Association, Inc.