Renin-angiotensin system revisited

Abstract

New components and functions of the renin-angiotensin system (RAS) are still being unravelled. The classical RAS as it looked in the middle 1970s consisted of circulating renin, acting on angiotensinogen to produce angiotensin I, which in turn was converted into angiotensin II (Ang II) by angiotensin-converting enzyme (ACE). Ang II, still considered the main effector of RAS was believed to act only as a circulating hormone via angiotensin receptors, AT1 and AT2. Since then, an expanded view of RAS has gradually emerged. Local tissue RAS systems have been identified in most organs. Recently, evidence for an intracellular RAS has been reported. The new expanded view of RAS therefore covers both endocrine, paracrine and intracrine functions. Other peptides of RAS have been shown to have biological actions; angiotensin 2-8 heptapeptide (Ang III) has actions similar to those of Ang II. Further, the angiotensin 3-8 hexapeptide (Ang IV) exerts its actions via insulin-regulated amino peptidase receptors. Finally, angiotensin 1-7 (Ang 1-7) acts via mas receptors. The discovery of another ACE2 was an important complement to this picture. The recent discovery of renin receptors has made our view of RAS unexpectedly complex and multilayered. The importance of RAS in cardiovascular disease has been demonstrated by the clinical benefits of ACE inhibitors and AT1 receptor blockers. Great expectations are now generated by the introduction of renin inhibitors. Indeed, RAS regulates much more and diverse physiological functions than previously believed.

Figure 1

A simplified view of the ‘classic’ circulating renin‐angiotensin system. Whole arrows () indicate pathways; the clinical significance of which has been demonstrated. Dashed arrow () indicates pathway deduced from animal or cell culture experiments, not yet conclusively shown to be clinically relevant.

Figure 2

The present view of the expanded renin‐angiotensin system. RPR, renin/prorenin receptor; Mas, mas oncogene, receptor for Ang 1–7; AT2R, angiotensin type 2 receptor; AT1R, angiotensin type 1 receptor, IRAP, insulin‐regulated aminopeptidase; Ang IV receptor AMPA, aminopeptidase A; AMPM, aminopeptidase M; ACE, angiotensin‐converting enzyme; ACE2, angiotensin‐converting enzyme 2; NEP, neutral endopeptidase.

Figure 3

Effects of angiotensin peptides and renin/prorenin mediated by their their corresponding receptors.

Figure 4

Schematic presentation of prorenin interacting with renin/prorenin receptor (RPR, in dimeric form), leading to activation of prorenin by displacement of the prosegment (). Activated renin then generates Ang I from angiotensinogen (AGT) and angiotensin‐convering enzyme generates Ang II from Ang I, and Ang II can then activate AT1 receptors on the same cell membrane. Signalling via extracellular signal‐regulated kinase (ERK) 1/2 leads to activation of genes. Modified from Nguyen 2007 [52].

Figure 5

Scheme of presently available renin‐angiotensin system inhibitors.