# Renin–angiotensin system activation and oxidative stress in hospitalized COVID-19 patients: a single-centre prospective observational study

## TL;DR

This study shows that worsening respiratory status in hospitalized COVID-19 patients is linked to changes in the renin-angiotensin system and endothelial dysfunction markers.

## Contribution

The study identifies specific RAS peptide dynamics and ADMA levels as potential indicators of disease progression in COVID-19.

## Key findings

- Patients with worsening respiratory status showed increased renin, Ang I, and Ang 1–7 levels and decreased Ang II/Ang I ratio.
- Higher ADMA and EASIX levels were observed in patients with respiratory deterioration, indicating endothelial dysfunction.
- Baseline ADMA levels independently predicted worse 28-day outcomes in hospitalized COVID-19 patients.

## Abstract

The renin–angiotensin system (RAS) plays a critical role in vascular homeostasis and inflammation, and its dysregulation has been implicated in the pathophysiology of COVID-19. We investigated the dynamics of RAS peptides and markers of endothelial dysfunction in relation to respiratory disease progression in hospitalized COVID-19 patients.

In this single-centre prospective observational study, 155 adult patients with confirmed SARS-CoV-2 infection were enrolled at hospital admission. Plasma levels of renin, angiotensin I (Ang I), angiotensin II (Ang II), angiotensin 1–7 (Ang 1–7), the Ang II/Ang I ratio (as a surrogate of ACE activity), and asymmetric dimethylarginine (ADMA)—a marker of endothelial dysfunction —were measured at baseline (D0) and day 3 (D3). Endothelial injury was further assessed using the Endothelial Activation and Stress Index (EASIX). Patients were stratified by respiratory trajectory using the WHO ordinal scale. Biomarker kinetics were analysed with baseline-adjusted regression models, and 28-day clinical status was evaluated using partial proportional-odds regression.

Of 155 patients, 89 (57%) experienced worsening respiratory status. These patients exhibited progressive RAS activation with higher renin and Ang I at D3 (p < 0.001), a decline in the Ang II/Ang I ratio (p < 0.001), and a rise in Ang 1–7 (p < 0.001). ADMA and EASIX levels increased in parallel, with significantly higher ADMA in worsening vs. non-worsening patients at D3 (0.72 [0.62–0.87] vs. 0.61 [0.50–0.70] µM/L; p < 0.001). Biomarker trajectories differed according to disease course, with significant interaction terms between baseline values and respiratory deterioration. At 28 days, outcomes were associated with renin, Ang I, Ang 1–7, and the Ang II/Ang I ratio, but not with Ang II. Elevated baseline ADMA also independently predicted worse prognosis.

Worsening respiratory status in COVID-19 is associated with delayed activation of the RAS, a shift toward the alternative Ang 1–7 pathway, and parallel increases in endothelial dysfunction markers. These findings suggest that serial measurements of RAS peptides and ADMA may aid in identifying high-risk phenotypes and inform personalized therapeutic strategies in COVID-19.

The online version contains supplementary material available at 10.1186/s40635-026-00857-w.