Physiology of the RAS axis
The RAS pathway is depicted in Figure 1. The RAS is a cascade of complex
polypeptides that were originally described in the context of
hypertension, cardiovascular, and renal disease. Research now shows that
RAS plays a central role in immunomodulation.8 Renin
is the rate-limiting enzyme of the RAS axis. It is secreted as a
pro-enzyme, prorenin. Renin converts circulating angiotensinogen into
angiotensin I. Angiotensin I is then broken down into Angiotensin II by
angiotensin-converting enzyme (ACE). Angiotensin II is the primary
effector molecule through its receptors - AT1 and AT2. Angiotensin II is
degraded by angiotensin-converting enzyme 2 (ACE2) into Ang (1-7).
While the ACE-Angiotensin II pathway exerts a pro-inflammatory effect,
ACE2-Ang(1-7) plays a role in immune tempering. Similarly, the effect of
angiotensin II on the AT1 receptor is mainly pro-inflammatory while the
action on the AT2 receptor is anti-inflammatory.9
Renin and prorenin exert a distinct proinflammatory effect through a
separate receptor - the prorenin receptor (PRR).10Apart from the effects of circulating RAS, tissue-specific RAS pathways
in the heart, lung, kidney, and blood vessels mediate organ-specific
inflammation; first described in the kidney.11