Potential compensatory upregulation of the alternative renin–angiotensin system in COVID-19 patients' saliva

COVID-19 is associated with immune dysregulation and alterations in the renin–angiotensin system (RAS), which contributes to inflammatory responses. As saliva is a reservoir for SARS-CoV-2 and a source of biomarkers, the study assessed the expression of RAS components and cytokines in saliva samples from COVID-19 patients. Saliva was collected from healthy controls and 109 symptomatic COVID-19 patients, recruited during the third wave of the COVID-19 pandemic from the Hospital Municipal de Aracatuba. RAS components gene expression was assessed by RT-qPCR, and soluble ACE2 and cytokine levels by ELISA. Data normality was assessed using Shapiro–Wilk test and between-group differences using the Mann–Whitney U test (p ≤ 0.05). Correlation analyses were performed using Spearman’s correlation test (p ≤ 0.05). The study was approved by the Research Ethics Committee of FOA/UNESP through Plataforma Brasil (approval number: 4.455.983). COVID-19 patients showed a significant increase in salivary gene expression of ACE2, AT2 receptor, and renin compared to healthy controls (p ≤ 0.05, p ≤ 0.05, and p ≤ 0.01, respectively), as well as higher salivary levels of soluble ACE2 and the cytokines TNF-α, IL-17, and IL-8 (p ≤ 0.0001, p ≤ 0.01, and p ≤ 0.05, respectively). We detected no expression of ACE, AT1 receptor, or angiotensinogen in either group. There were no changes in Mas receptor, IL-6, or IFN-γ expression. Correlation analysis demonstrated a positive association of soluble ACE2 with TNF-α (r = 0.3786; p = 0.0095) and a negative association with IL-8 (r = -0.3864; p = 0.0219) and IL-6 (r = -0.3440; p = 0.0117). AT2 receptor expression also correlated positively with TNF-α levels (r = 0.3024; p = 0.0012). Therefore, SARS-CoV-2 infection was accompanied by increased salivary ACE2 and AT2 receptor expression, which correlated with inflammatory cytokine release, suggesting a possible compensatory upregulation of the local alternative RAS in response to oral tissue inflammation.