# Circulating factors as a mechanism of improvements in vascular endothelial function with inorganic nitrate in patients with chronic kidney disease

> **NIH NIH R03** · UNIVERSITY OF COLORADO · 2024 · $117,375

## Abstract

PROJECT SUMMARY
Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD).
Vascular endothelial dysfunction is a key antecedent to CVD in patients with CKD. A primary mechanism of
endothelial dysfunction in CKD is a decline in the vasoprotective molecule nitric oxide (NO). Reactive
oxygen species (ROS)-related oxidative stress, a key source of which is mitochondria, mediates reductions
in NO bioavailability in CKD. Establishing new therapies to enhance NO bioavailability and lower ROS-related
oxidative stress to improve endothelial function in patients with CKD is a biomedical research priority.
Targeting the nitrate-nitrite-NO pathway represents a promising approach for enhancing NO bioavailability
and improving endothelial function in CKD. I have shown in older adults without CKD that targeting the nitrate-
nitrite-NO pathway with inorganic nitrite (sodium nitrite) improves NO-mediated endothelial function. The
improvements are associated with changes in circulating factors in plasma that reduce endothelial cell total
and mitochondria-specific ROS bioactivity. Sodium nitrite also alters the plasma metabolome, and changes in
select metabolites with treatment are associated with lower plasma-induced endothelial cell ROS bioactivity.
To translate these findings to CKD, I am completing a randomized clinical trial testing the effects of 3 months of
treatment with nitrate-rich beetroot juice vs. placebo (nitrate-depleted beetroot juice) for improving endothelial
function in individuals with CKD (K01DK115524). My preliminary findings suggest that nitrate-rich beetroot
juice improves NO-mediated endothelial function. My preliminary results also suggest nitrate-rich beetroot
juice may change circulating factors in plasma to improve endothelial cell function, as shown by an
increased acetylcholine (ACh)-stimulated NO production and reduced ROS bioactivity in human aortic
endothelial cells (HAECs) exposed to plasma from subjects taken before/after active treatment vs. placebo.
The purpose of this R03 application is to leverage samples from my K01-supported clinical trial to show
changes in ‘circulating factors’ as a novel mechanism contributing to improvements in endothelial function
with nitrate-rich beetroot juice supplementation in patients with CKD and to identify the specific circulating
molecular transducers of the benefits of nitrate-rich beetroot juice on endothelial function in CKD.
Aim 1: To assess before/after 3 months of nitrate-rich beetroot juice or placebo (double-blind, randomized) in
men and women ≥50 years of age with stage II-IV CKD: i) ACh-stimulated NO production; and ii) total and
mitochondria-specific ROS bioactivity in HAECs exposed to plasma from subjects before/after the intervention.
Aim 2: a) To determine the effects of nitrate-rich beetroot juice on metabolites in plasma via targeted
metabolomics analysis of plasma samples taken before and after nitrate-rich beetroot juice treatme...

## Key facts

- **NIH application ID:** 10950532
- **Project number:** 1R03DK140289-01
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** Matthew J Rossman
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $117,375
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10950532

## Citation

> US National Institutes of Health, RePORTER application 10950532, Circulating factors as a mechanism of improvements in vascular endothelial function with inorganic nitrate in patients with chronic kidney disease (1R03DK140289-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10950532. Licensed CC0.

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