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ACE2 and Angiotensin-(1-7) in Hypertensive Renal Disease

The recently discovered angiotensin-converting enzyme-related carboxypeptidase 2 (ACE2)-[Angiotensin-(1-7)(Ang-(1-7)]-Mas receptor axis has an opposing function to that of the ACE-Angiotensin II (Ang II)-Angiotensin type 1 (AT1) receptor axis. Ang-(1-7) is present in the kidneys at concentrations comparable to those of Ang II and is associated with vasodilation, modulation of sodium and water transport, and stimulation of nitric oxide (NO) synthase. Ang-(1-7) also acts as a physiological antagonist of Ang II by counterbalancing the Ang II-mediated intracellular signaling pathway. In a hypertensive model, increased ACE and decreased ACE2 along with a higher ACE/ACE2 ratio in hypertensive kidneys appeared to favor Ang II generation, leading to hypertensive renal damage. In addition, the administration of a selective Ang-(1-7) receptor blocker or an ACE2 inhibitor was associated with worsening of hypertension and renal function. Ang-(1-7)-mediated increases in renal blood flow were abolished by blockade of the Mas receptor and by inhibition of prostaglandin release and NO in spontaneously hypertensive rats and in Wistar-Kyoto controls. Further research on the function of the ACE2-Ang-(1-7)-Mas receptor axis could lead to a novel target for inhibiting kidney disease progression.


Introduction
The renin-angiotensin system (RAS) is a pivotal mediator of renal and vascular homeostasis. Its systemic actions include the regulation of blood pressure, natriuresis, and blood volume control. The RAS also plays an important role at a local level, regulating regional blood flow and controlling trophic and fibrotic responses to a range of stimuli. The RAS is composed of a number of different regulatory components and effector molecules. Angiotensin II (Ang II) acts by binding to Ang II type 1 (AT1) and Ang II type 2 (AT2) receptors. The angiotensin-converting enzyme found in most tissues, with its highest expression observed in the kidneys, endothelium, and heart 4,5) . The extracellular surface of the ACE2 enzyme contains a single catalytic metallopeptidase domain that shares 42% sequence identity and 61% sequence similarity with the N-terminal catalytic domain of somatic ACE. ACE2 is an exopeptidase that catalyzes the conversion of Ang I to the nonapeptide Ang-(1-9) and the conversion of Ang II to the heptapeptide Ang-(1-7). The primary role of ACE2 is converting Ang II into Ang-(1-7) with an efficacy > 400-fold greater than that of the hydrolytic action of ACE2 in forming Ang-(1-9) 6) . ACE2 is associated with a reduction in Ang II and an increase in Ang-(1-7) levels. ACE2 protein levels are significantly decreased in the kidneys of hypertensive patients, and patients with late diabetic nephropathy 7,8) .
The heptapeptide Ang-(1-7), generated from either Ang I or Ang II, acts by opposing the vasoconstrictor, proliferative, and profibrotic actions of Ang II in the circulation and in cardiac, vascular, and renal tissues 9,10) . In a type 2 diabetic animal model, Ang-(1-7) attenuated Ang II-mediated NAD(P)H oxidase activation and reactive oxygen species production in diabetic glomeruli and mesangial cells were

Effects of ACEI and angiotensin II receptor blockers (ARBs) partly depend on ACE2 and Ang-(1-7)
ACE inhibitors and receptor blockers can affect the are expressed in the renal proximal tubules, but inside the glomeruli, they are mainly expressed in the podocytes 14) .
In normal kidneys, high constitutive levels of ACE2 and a higher ACE2/ACE ratio may be associated with an increase in the Ang II breakdown system compared to Ang II generation, which may be important for maintaining the normal physiological and biological effects of Ang II. In contrast, increased ACE and decreased ACE2 with a higher to Ang-(1-7) (and, by association, ACE2) was augmented in the following conditions: low salt diet; renin transgenic hypertensive rats; and Ang II infusion. In all of these conditions, endogenous RAS was stimulated.

Sexual differences in blood pressure related to the ACE2-Ang-(1-7)-Mas axis
Male SHR have elevated blood pressure and a higher incidence of albuminuria compared to age-matched female SHR 19,20) . Treatment of male and female SHR with enalapril reduced blood pressure to similar levels in both sexes, indicating that both hypertension and sex differences in blood pressure are RAS mediated 21)

Conclusions
• ACE2 is a functional component of the RAS; ACE2 metabolizes Ang II and produces Ang-(1-7), thereby contributing to regulation of blood pressure and progression of renal disease.
• Effects of ACEI and ARB partly depend on ACE2 activation.
• The vascular response to Ang-(1-7) (and by association, ACE2) is augmented in conditions where the endogenous RAS has been stimulated.
• Targeting the ACE2-Ang-(1-7)-Mas receptor axis may be a novel therapeutic strategy for hypertension and diabetic kidney disease.