ACE and ACE2 in kidney disease

Abstract

Renin angiotensin system (RAS) activation has a significant influence on renal disease progression. The classical angiotensin-converting enzyme (ACE)-angiotensin II (Ang II)-Ang II type 1 (AT1) axis is considered to control the effects of RAS activation on renal disease. However, since its discovery in 2000 ACE2 has also been demonstrated to have a significant impact on the RAS. The synthesis and catabolism of Ang II are regulated via a complex series of interactions, which involve ACE and ACE2. In the kidneys, ACE2 is expressed in the proximal tubules and less strongly in the glomeruli. The synthesis of inactive Ang 1-9 from Ang I and the catabolism of Ang II to produce Ang 1-7 are the main functions of ACE2. Ang 1-7 reduces vasoconstriction, water retention, salt intake, cell proliferation, and reactive oxygen stress, and also has a renoprotective effect. Thus, in the non-classical RAS the ACE2-Ang 1-7-Mas axis counteracts the ACE-Ang II-AT1 axis. This review examines recent human and animal studies about renal ACE and ACE2.

Keywords: Angiotensin-converting enzyme; Angiotensin-converting enzyme 2; Diabetic nephropathy; Kidney disease; Renin angiotensin system.

Figure 1

Roles of angiotensin-converting enzyme and angiotensin-converting enzyme 2 in the renin angiotensin system. Angiotensinogen is cleaved by renin to form angiotensin I (Ang I), which is converted to Ang II by ACE. The main function of ACE2 is to synthesize inactive Ang 1-9 from Ang I and to produce the vasodilatory and antiproliferative molecule Ang 1-7 from Ang II. Ang I acts a substrate for neprilysin, which cleaves it to form Ang 1-7. Ang II binds to the Ang II type 1 receptor (AT1-R) and AT2-R. The Mas receptor (MAS-R) is a specific receptor for Ang 1-7. The ACE2-Ang 1-7-MAS axis counteracts the effects of the ACE-Ang II-AT1 axis. ACE: Angiotensin-converting enzyme; NO: Nitric oxide; NEP: Neprilysin; ROS: Reactive oxygen species.

Figure 2

Images obtained with confocal microscopy of triple immunofluorescence staining of angiotensin-converting enzyme (green), angiotensin-converting enzyme 2 (red), and nuclei (DAPI; blue) in kidney specimens. In healthy subjects, marked co-localization of ACE and ACE2 (yellow) was observed in the apical brush borders of the proximal tubules (A). Both ACE and ACE2 were also present in the glomeruli, but the glomeruli exhibited weaker staining than the proximal tubules (A). In diabetic kidneys, stronger ACE expression and weaker ACE2 expression were detected in the proximal tubules, and no marked colocalization of ACE and ACE2 was observed (B); however, similar ACE and ACE2 staining patterns were seen in patients with minimal change nephrotic syndrome (MCNS) and healthy controls (C). Adapted with permission from Mizuiri et al[33]. ACE: Angiotensin-converting enzyme.