The vasoprotective axes of the renin-angiotensin system: Physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases

Abstract

The renin-angiotensin system (RAS) is undisputedly one of the most prominent endocrine (tissue-to-tissue), paracrine (cell-to-cell) and intracrine (intracellular/nuclear) vasoactive systems in the physiological regulation of neural, cardiovascular, blood pressure, and kidney function. The importance of the RAS in the development and pathogenesis of cardiovascular, hypertensive and kidney diseases has now been firmly established in clinical trials and practice using renin inhibitors, angiotensin-converting enzyme (ACE) inhibitors, type 1 (AT₁) angiotensin II (ANG II) receptor blockers (ARBs), or aldosterone receptor antagonists as major therapeutic drugs. The major mechanisms of actions for these RAS inhibitors or receptor blockers are mediated primarily by blocking the detrimental effects of the classic angiotensinogen/renin/ACE/ANG II/AT₁/aldosterone axis. However, the RAS has expanded from this classic axis to include several other complex biochemical and physiological axes, which are derived from the metabolism of this classic axis. Currently, at least five axes of the RAS have been described, with each having its key substrate, enzyme, effector peptide, receptor, and/or downstream signaling pathways. These include the classic angiotensinogen/renin/ACE/ANG II/AT₁ receptor, the ANG II/APA/ANG III/AT₂/NO/cGMP, the ANG I/ANG II/ACE2/ANG (1-7)/Mas receptor, the prorenin/renin/prorenin receptor (PRR or Atp6ap2)/MAP kinases ERK1/2/V-ATPase, and the ANG III/APN/ANG IV/IRAP/AT₄ receptor axes. Since the roles and therapeutic implications of the classic angiotensinogen/renin/ACE/ANG II/AT₁ receptor axis have been extensively reviewed, this article will focus primarily on reviewing the roles and therapeutic implications of the vasoprotective axes of the RAS in cardiovascular, hypertensive and kidney diseases.

Keywords: ACE2; Alamandine; Angioprotectin; Angiotensin (1–7); Angiotensin 1-converting enzyme; Angiotensin II; Cardiovascular disease; Dipeptidyl peptidase III; Hypertension.

Figure 1

Classical and new paradigms of the evolving renin-angiotensin system. (1): receptor axis. (2): the ANG the classical angiotensinogen/renin/ACE/ANG II/AT₁ receptor/NO/cGMP axis. (3): the ANG I/ANG II/ACE2/ANG (1–7)/Mas II/APA/ANG III/AT₂ receptor axis. (4): the prorenin/renin/prorenin receptor (PRR or ATP6ap2)/MAP kinases receptor/IRAP axis. Modified ERK1/2/V-ATPase axis. (5): the ANG III/APN/ANG IV/AT₄ from reference [5] with permission.

Figure 2

In vitro autoradiographic localization of AT₁ and AT₂ receptors in the human kidney and renal artery using [¹²⁵I]-[Sar¹,Ile⁸]-ANG II as the radioligand. A & E: total ANG II (AT₁ and AT₂) receptors. C & F: AT₁ receptor binding in the presence of 10 μM of the AT₂ receptor blocker PD123319 (10 μM). D & G: AT₂ receptor binding in the presence of 10 μM of the AT₁ receptor blocker losartan. Modified from reference [100] with permission.

Figure 3

In vitro autoradiographic localization of AT₁ and AT₂ receptors in bovine (A–D), monkey (E–H) and human adrenal glands (I–L) using [¹²⁵I]-[Sar¹,Ile⁸]-ANG II as the radioligand. A, E & I: total ANG II (AT₁ and AT₂) receptors. B, F & J: AT₁ receptor binding in the presence of 10 μM of the AT₂ receptor blocker PD123319 (10 μM). C, G & K: AT₂ receptor binding in the presence of 10 μM of the AT₁ receptor blocker losartan. D, H & L: nonspecific binding in the presence of 10 μM of unlabled ANG II. Modified from [99] with permission.

Figure 4

In vitro autoradiographic localization of ANG (1–7) (A) and AT₄ receptors (B) in the rat kidney using [¹²⁵I]-ANG (1–7) and [¹²⁵I]-ANG (3–8) as the radioligands, respectively. Modified from [5] and [23] with permission.

Figure 5

Dose-dependent pressor and renal cortical and medullary vasoconstrictor responses to intravenous infusion of increasing concentrations of ANG II, ANG III, and ANG IV. ANG II, ANG III, and ANG IV increased mean arterial pressure (MAP) and decreased renal cortical blood flow (CBF) in a dose-dependent manner, exhibiting potency in the order: ANG II > ANG III > ANG IV. ANG II and ANG III also decreased renal medullary blood flow (MBF) at higher doses, whereas ANG IV had no effect. P < 0.05 vs. baseline ANG IV response (*), vs. baseline ANG III response (+), and vs. baseline ANG II response (#). Reproduced from [23] with permission.