Dysregulated renin-angiotensin system (RAS) signaling contributes to elevated blood pressure (BP), inflammation, and organ damage in systemic arterial hypertension (HTN). We have demonstrated that 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, we 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 (1-7)] 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 macrophage number and down-regulated pro-inflammatory genes in SHR lungs, with lower expression of lung pro-inflammatory genes correlating with lower circulating levels of ACE2. Serum analysis in healthy and 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, this study provides a mechanistic link between inflammatory lung diseases (such as COVID-19) and hypertension as a major risk factor.
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The cover of this issue of Clinical Science shows representative kidney coronal sections of male mice stained with hematoxylin and eosin in Agt-KO mice, with hydronephrosis being identified with a yellow asterisk. Read more in 'Renal damage-induced hepcidin accumulation contributes to anemia in angiotensinogen-deficient mice' from André F. Rodrigues and colleagues at: https://doi.org/10.1042/CS20241789
Restoring lung renin-angiotensin system balance through blood pressure control
Gabriela Catão D. Braga, Joao Carlos Ribeiro-Silva, Andreia Boaro, Flavia Leticia Martins, Thais Mauad, Caio A.M. Tavares, Lisete Ribeiro Teixeira, Bruno Caramelli, Adriana C.C. Girardi; Restoring lung renin-angiotensin system balance through blood pressure control. Clin Sci (Lond) 12 February 2025; 139 (03): 215–227. doi: https://doi.org/10.1042/CS20241155
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