Angiotensin II revisited: new roles in inflammation, immunology and aging

Abstract

That the renin-angiotensin system (RAS) is involved in regulation of blood pressure, vasoconstriction, sodium intake and potassium excretion is well established. Studies in the last few years have however documented new roles for this molecule as a pro-inflammatory molecule and more recently as a possible pro-fibrotic agent that contributes to progressive deterioration of organ function in disease. Binding of Ang II to its receptors (in particular AT(1)) mediates intracellular free radical generation that contributes to tissue damage by promoting mitochondrial dysfunction. Blocking Ang II signalling protects against neurodegenerative processes and promotes longevity in rodents. Altogether these findings open the unanticipated perspective for exploring Ang II signalling in therapeutic interventions in inflammatory diseases and aging-related tissue injury. This review extends from the discovery of Ang II and its implications in renal and cardiovascular physiology to cover the roles of the system in inflammation, tissue injury, autoimmunity, oxidative stress and aging.

Figure 1. The renin–angiotensin system (RAS)

Renin, a protease produced in the kidney, cleaves the AGT to produce the inactive decapeptide angiotensin I. Cleavage of angiotensin I by ACE or alternatively by chymase produces the active octapeptide Ang II that acts via AT₁ and AT₂ receptors. Ang II levels are also regulated by ACE2 that cleaves Ang II to produce the heptapetide vasodilatory Ang 1–7. AGT, angiotensinogen; ACE, angiotensin converting enzyme; AT₁R, angiotensin type 1 receptor; AT₂R, angiotensin type 2 receptor; ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker.

Figure 2. The role of Ang II on tissue inflammation

Angiotensin II via AT₁ receptor signalling in immune cells as well as mesangial cells and vascular smooth muscle cells contributes to the localized activation of the immune system.

Figure 3. Ang II signalling affects aging

Ang II increases ROS generation and reduces the expression of the pro-survival gene Sirt3, affecting transcription of antioxidant enzymes. As depicted in red, the disruption of AT_1A receptor preserves mitochondrial and cellular wellness and promotes longevity by modulating ROS production and sirtuin expression.