The role of ACE2 in pulmonary diseases--relevance for the nephrologist

Abstract

The renin–angiotensin system (RAS) is a central regulator of cardiovascular and renal functions and plays a key role in the pathophysiology of various cardiovascular and renal diseases. The RAS consists of a series of enzymatic reactions culminating in the generation of angiotensin II (Ang II) in plasma as well as in various tissues including the heart and kidneys. The discovery of angiotensinconverting enzyme 2 (ACE2) had added a new dimension to the RAS [1–5]. Human and rodent ACE2 are similar proteins containing 805 amino acids that include an N-terminal signal sequence, a single active-site catalytic region and a C-terminal hydrophobic membrane-anchor region [2,3,5]. ACE2 functions predominantly as a carboxymonopeptidase with a substrate preference for hydrolysis between proline and a hydrophobic or basic C-terminal residue [6]. Both ACE and ACE2 are endothelium-bound carboxypeptidases with ACE2 protein being highly expressed in the heart and kidney, and in the kidney, ACE2 is expressed in renal tubular epithelium, vascular smooth muscle cells of the intrarenal arteries and in the glomeruli [1,2,5]. Both enzymes can be cleaved by distinct metalloproteases located on the cell surface and released as soluble forms [3]. Despite sharing many biochemical properties with ACE, ACE2 is insensitive to classical ACE inhibitors [2,5]. Intriguingly, the location of the ACE2 gene on the X-chromosome implies that gender differences in the RAS and cardiovascular physiology may be linked to the ACE2 gene. ACE2 can not only cleave Ang I to generate the inactive Ang 1-9 peptide ACE2 but also directly metabolize Ang II to generate Ang 1-7 [7,3,6]. Ang 1-7 functions essentially as a physiological antagonist of Ang II signalling in the cardiovascular system [8,3] and in the kidneys! [9,10]. ACE2 can potentially me-