The Renin-Angiotensin-Aldosterone System (RAAS): Beyond Cardiovascular Regulation

Abstract

The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in regulating cardiovascular function, fluid balance, and blood pressure. Recent research has revealed the RAAS's influence extends beyond cardiovascular physiology, encompassing key roles in inflammation, fibrosis, immune regulation, cancer progression, and organ-specific disease mechanisms. This review provides a comprehensive overview of classical and alternative RAAS pathways, focusing on the dual roles of angiotensin II (Ang II) and angiotensin-(1-7) (Ang 1-7), mediated through AT1R, AT2R, MasR, and MrgD receptors. We discuss molecular signaling cascades, including mitochondrial, nuclear, and caveolae-mediated mechanisms, and explore the impact of RAAS modulation on hepatic fibrosis, vascular remodeling, and autoimmune inflammation. Genetic models and emerging pharmacologic strategies illustrate tissue-specific RAAS actions, emphasizing the therapeutic potential of enhancing the ACE2/Ang 1-7/Mas axis while inhibiting the deleterious ACE/Ang II/AT1R signaling. Furthermore, we highlight implications for veterinary medicine, particularly in canine chronic inflammatory enteropathies, where RAAS dysfunction may contribute to treatment resistance. Understanding RAAS complexity and inter-receptor crosstalk is essential for developing new therapeutic strategies targeting cardiovascular, hepatic, and inflammatory diseases in both human and veterinary contexts.

Keywords: angiotensin-converting enzyme system (ACE system); angiotensinogen; inflammation; the renin–angiotensin–aldosterone system (RAAS).

Figure 1

Schematic representation of the renin–angiotensin–aldosterone system (RAAS), highlighting two main counter-regulatory pathways. The ACE/Ang II/AT1R pathway promotes vasoconstriction, aldosterone production, antidiuretic hormone (ADH) release, oxidative stress, fibrosis, hypertrophy, and contributes to cardiovascular diseases. In contrast, the ACE/ Ang-(1-7)/MAS receptor pathway exerts protective effects, including vasodilation, blood pressure reduction, neuroprotection, and overall positive cardiovascular outcomes. Additionally, Ang II binding to AT2 receptors attenuates oxidative stress and inflammation through ERK and PI3K/AKT signaling pathways. The balance between these pathways is essential for cardiovascular homeostasis and disease prevention. (Ang = angiotensinogen; ERK = extracellular signal-regulated kinase; PI3K = phosphoinositide 3-kinase; AKT = protein kinase B; NO = nitric oxide; COX-2 = cyclo-oxygenase-2; FOXO1 = forkhead box O1).