The contributory role of microbial metabolite in the pathogenesis of CKD-dependent vascular calcification

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The long term objective of this research proposal is to determine the molecular mechanisms of vascular calcification in order to identify novel target(s) for the treatment of chronic kidney disease (CKD)-dependent vascular calcification. Vascular calcification is closely associated with cardiovascular mortality in patients with CKD. In fact, more than half of all deaths in CKD patients can be attributed to cardiovascular diseases. Our previous study revealed that activation of a bile acid nuclear receptor, FXR, strongly attenuates CKD- dependent vascular calcification in animal models though an unknown mechanism. Recently, our metabolomic approach has identified that levels of a microbial bile acid metabolite, deoxycholic acid (DCA), are highly associated with an increased risk for higher coronary artery calcification (CAC) volumes and lower lumbar bone mineral density (BMD) in human patients and mice with CKD. We hypothesized that DCA generated by gram-positive bacteria causes CKD-dependent vascular calcification. Our hypothesis is also supported by the following evidence derived from a series of preliminary results from our lab: 1) CKD increases levels of circulating DCA. 2) FXR activation by its agonists preferentially reduces levels of DCA and a precursor of DCA, cholic acid. 3) FXR knockout mice with vascular calcification have significantly higher levels of DCA. 4) CKD alters gut bacteria populations and increases levels of the DCA-producing bacteria. 5) Activation of FXR normalizes the alteration of gut bacteria populations by CKD. 6) DCA but not other bile acids induces mineralization of VSMCs through TGR5-PKA--catenin signaling. To determine the pivotal role of microbial DCA in the pathogenesis of vascular calcification, we propose 3 specific aims: Specific Aim 1: Examine the molecular mechanism by which DCA induces vascular calcification in vitro. Specific Aim 2: A) Examine whether alterations of circulating DCA levels and gut bacteria populations influence CKD-dependent vascular calcification in vivo. B) Examine whether modulation of intestinal bacteria affects CKD-dependent vascular calcification in vivo. Specific Aim 3: Examine whether TGR5-PKA--catenin signaling contributes to CKD- dependent vascular calcification in vivo.