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

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $469,245

## Abstract

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.

## Key facts

- **NIH application ID:** 9834974
- **Project number:** 5R01HL133545-03
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Makoto Miyazaki
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $469,245
- **Award type:** 5
- **Project period:** 2017-12-22 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9834974

## Citation

> US National Institutes of Health, RePORTER application 9834974, The contributory role of microbial metabolite in the pathogenesis of CKD-dependent vascular calcification (5R01HL133545-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9834974. Licensed CC0.

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