# The mechanism of uremia induced vascular calcification

> **NIH VA I01** · RLR VA MEDICAL CENTER · 2020 · —

## Abstract

The prevalence of Chronic Kidney Disease (CKD) in the Veteran population is estimated to be a third higher
than in the general population and the Veterans Health Administration currently cares for over 200,000
Veterans with moderate to severe kidney disease. The leading cause of death in patients with CKD is
cardiovascular disease. Vascular calcification is highly prevalent in chronic kidney disease (CKD) and is a
major cause of cardiovascular morbidity and mortality. Work done during our previous VA Merit Awards in
vitro and in vivo in our CKD animal model, have demonstrated that vascular smooth muscle cells (VSMC) can
de-differentiate to a more synthetic, osteo-chondrocytic cell with upregulation of RUNX2. This renders cells
that can calcify in a manner similar to bone. Calcifying VSMC release matrix vesicles, small exosomes filled
with calcium, phosphorus, protein and micro RNA (miRNA). Our bioinformatic analyses of miRNA arrays
comparing VSMC and matrix vesicles have identified altered expression of multiple miRNA that regulate genes
involved in VSMC phenotypic change/calcification, intracellular calcium (iCa) homeostasis, and oxidative stress
pathways. Consistent with these findings, in vivo in our animal model of slowly progressive CKD there is also
progressive increases in oxidative stress and iCa in VSMC. We hypothesize that Increased intracellular
calcium (iCa) and oxidative stress are additive in inducing arterial calcification in CKD. To test this hypothesis
in Aim 1, we propose to determine the relationship between increased intracellular calcium (iCa) and oxidative
stress in calcifying VSMC from CKD versus NL animals. We will alter the iCa and determine the effect on
oxidative stress, and conversely, decrease oxidative stress and determine if this alters iCa and if calcium
channels/transporters are oxidized leading to altered function. In Aim 2, we will determine if the combination of
decreased iCa and decreased oxidative stress alters CKD VSMC matrix vesicle protein content, miRNA profile,
and modulation of the recipient VSMC osteogenic phenotype. In Aim 3, we will determine if the administration
of the combination of agents to reduce both iCa and oxidative stress can prevent and/or treat arterial
calcification in vivo in our rat model of progressive CKD. These studies will determine if the vicious cycle of
increased iCa and increased oxidative stress accelerate vascular calcification in CKD, the mechanisms by
which this happens, the role of matrix vesicle miRNA, and if dual blockade can prevent and/or stop arterial
calcification that plaques patients with CKD. Our long term goal is to improve the cardiovascular health of
Veterans with CKD.

## Key facts

- **NIH application ID:** 9814665
- **Project number:** 5I01BX001471-08
- **Recipient organization:** RLR VA MEDICAL CENTER
- **Principal Investigator:** Sharon M Moe
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2012-04-01 → 2020-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9814665

## Citation

> US National Institutes of Health, RePORTER application 9814665, The mechanism of uremia induced vascular calcification (5I01BX001471-08). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9814665. Licensed CC0.

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