Restoring lung renin-angiotensin system balance through blood pressure control

Author(s)

Braga, Gabriela Catao D. ; Ribeiro-Silva, Joao Carlos ; Boaro, Andreia ; Martins, Flavia Leticia ; Mauad, Thais ; Tavares, Caio A. M. ; Teixeira, Lisete Ribeiro ; Caramelli, Bruno ; Girardi, Adriana C. C.

• Document type: Journal article
• Source: Clinical Science; v. 139, n. 3, p. 13-pg., 2025-02-01.

Abstract

Dysregulated renin-angiotensin system (RAS) signaling contributes to elevated blood pressure inflammation, and organ damage in systemic arterial hypertension (HTN). We have demonstrated hypertensive humans and rats exhibit higher expression of classic RAS components and lower expression of counterregulatory RAS components in the lungs compared with normotensive counterparts. Here, investigated whether BP control could restore the balance between classic [angiotensin I-converting enzyme 2 (ACE)/angiotensin II (Ang II)] and counterregulatory [angiotensin I-converting enzyme 2 (ACE2)/Ang RAS, thereby mitigating lung inflammation. Male spontaneously hypertensive rats (SHRs) were treated with either losartan or amlodipine, both of which effectively reduced BP. These interventions up-regulated lung Ace2 and down-regulated Ace gene expression. Pulmonary membrane ACE2 abundance and activity were higher in losartan- and amlodipine-treated SHRs than in vehicle-treated SHRs, whereas ACE protein and function remained unchanged. Drug-treated SHRs exhibited lower levels of lung Ang II and higher levels of Ang (1-7) than vehicle-treated SHRs. Rebalancing the pulmonary RAS remarkably reduced macro- phage number and down-regulated pro-inflammatory genes in SHR lungs, with lower expression of pro-inflammatory genes correlating with lower circulating levels of ACE2. Serum analysis in healthy hypertensive individuals supported these findings, showing higher ACE2 levels in uncontrolled compared with controlled hypertension and normotension. Collectively, these findings suggest that high blood pressure may induce lung inflammation via an ACE/ACE2 imbalance. BP control with either an RAS inhibitor or a calcium channel blocker rebalances RAS in SHR lungs and alleviates inflammation. Furthermore, study provides a mechanistic link between inflammatory lung diseases (such as COVID-19) and hypertension as a major risk factor. (AU)

• FAPESP's process: 20/05338-3 - Modulation of ACE2 in experimental hypertension and in response to treatment with ACE inhibitors and ARBs: potential implications for COVID-19 severity and therapeutic targets
• Grantee: Adriana Castello Costa Girardi
• Support Opportunities: Regular Research Grants
• FAPESP's process: 21/14534-3 - Pleiotropic effects of antidiabetic agents and their pharmacological targets: renoprotective mechanisms beyond glycemic control
• Grantee: Adriana Castello Costa Girardi
• Support Opportunities: Research Projects - Thematic Grants