In the past few years the understanding of the renin-angiotensin system (RAS) has improved, helping to better define the role of this system in physiological conditions and in human diseases. Besides Angiotensin (Ang) II, the biological importance of other Ang fragments was progressively evidenced. In this regard, Angiotensin- (Ang-) (1-7) was recognized as a biologically active product of the RAS cascade with a specific receptor, the G-protein-coupled receptor Mas, and that is mainly formed by the action of the angiotensin-converting enzyme (ACE) homolog enzyme, ACE2, which converts Ang II into Ang-(1-7). Taking into account the biological effects of these two mediators, Ang II and Ang-(1-7), the RAS can be envisioned as a dual function system in which the vasoconstrictor/proliferative or vasodilator/antiproliferative actions are primarily driven by the balance between Ang II and Ang-(1-7), respectively. In this paper, we will discuss our current understanding of the ACE2/Ang-(1-7)/Mas axis of the RAS in renal physiology and in the pathogenesis of primary hypertension and chronic kidney disease.
In the past few years the understanding of the renin-angiotensin system (RAS) has improved, helping to better define the role of this system in physiological conditions and in human diseases. Following the seminal study of Schiavone and coworkers [
The identification of the angiotensin-converting enzyme (ACE) homologue, ACE2, as the main Ang-(1-7)-forming enzyme was essential to establish a preferential enzymatic pathway for the production of this angiotensin peptide [
Further support for the relevance of Ang-(1-7) was achieved with the description of the orphan receptor Mas as a functional ligand site for this angiotensin [
It is now conceived that the RAS axis formed by ACE2, Ang-(1-7), and Mas is able to counter balance many of the well-established actions of the ACE-Ang II-AT1 receptor axis [
This paper will briefly highlight recent findings concerning the renal effects of the ACE2-Ang-(1-7)-Mas axis in renal physiology and discuss its potential role in disease states.
A growing body of evidence supports the relevance of Ang-(1-7) for the regulation of renal function. Ang-(1-7) is present in the kidney at concentrations that are comparable to Ang II [
It should be pointed that there are gender differences in renal activity of ACE2 and in the mRNA expression for this enzyme at renal tissue. In this regard, Ji and coworkers showed that ovariectomy decreased ACE2 protein (30%) and mRNA expression (36%) in renal wrap hypertension in rats, while 17-beta-estradiol replacement prevented these effects [
Ang-(1-7) is the main product obtained in preparations of isolated proximal tubules and exists in urine at higher concentrations than Ang II [
Many studies have addressed the complexity of renal actions of Ang-(1-7) [
On the other hand, our group and other investigators have observed an antidiuretic/antinatriuretic effect induced by Ang-(1-7), especially in water-loaded animals [
The physiological relevance of Ang-(1-7) was further corroborated by the demonstration that Ang-(1-7) is an endogenous ligand for the G-protein-coupled receptor Mas in the kidney [
Beside important tubular actions, Ang-(1-7) also contributes to renal hemodynamic regulation. The ability of the kidney to generate high intratubular and interstitial concentrations of Ang II and Ang-(1-7) allows the kidney to regulate intrarenal levels of these angiotensins in accord with the homeostatic needs for the regulation of renal hemodynamics, tubular reabsorption, and sodium balance. When the RAS is inappropriately stimulated, high intrarenal Ang II levels, acting on AT1 receptors, can lead to both systemic and glomerular capillary hypertension, which can induce hemodynamic injury to the vascular endothelium and glomerulus [
Experimental studies have also indicated a role for the Ang-(1-7)-Mas interaction in the regulation of matrix proteins deposition in the heart and liver [
Although a protective role for Ang-(1-7) in renal fibrosis remains speculative, our findings in animals with genetic deletion of receptor Mas support this hypothesis [
In keeping with this possibility, recent studies suggested a protective role for ACE2 in the kidney. Kidney diseases have been associated with a reduction in renal ACE2 expression, possibly facilitating the damaging effects of Ang II. Acquired or genetic ACE2 deficiency also appears to exacerbate renal damage and albuminuria in experimental models, supporting this hypothesis [
On the other hand, some studies pointed to a deleterious role for Ang-(1-7) at renal system. For instance, the study of Esteban and coworkers using mice with genetic deletion of receptor Mas showed very discrepant results in relation to renal function when compared to our findings [
Agonists and antagonists of the Ang-(1-7)-Mas axis probably possess a therapeutic potential for the modulation of sodium and water excretion in many physiologic and pathologic renal conditions, such as arterial hypertension, nephrogenic diabetes insipidus, glomerular diseases, chronic kidney disease (CKD), and diabetic nephropathy (see [
In pediatric patients, Simões e Silva and coworkers have reported significant differences among circulating Ang II and Ang-(1-7) levels in renovascular disease and in primary hypertension [
In addition, Simões e Silva et al. have demonstrated a significant increase in plasma Ang-(1-7) and Ang II levels among hypertensive children with CKD stage III when compared to normotensive CKD patients with the same stage of renal dysfunction [
Another important aspect to be considered is the elevation of plasma Ang-(1-7) during chronic RAS inhibition [
The current evidence supports the existence of a counterregulatory axis within the RAS formed mainly by the ACE2-Ang-(1-7)-receptor Mas axis. The primary function of this axis is to oppose the effects of the major component of the RAS, Ang II. Experimental and clinical studies have demonstrated a role for the ACE2/Ang-(1-7)/Mas axis in the regulation of renal function, in arterial hypertension, and in the progression of CKD. Figure
Proposed mechanisms for the role of ACE-Ang II-AT1 receptor axis in excess of ACE2-Ang-(1-7)-Mas receptor axis at renal level.