ACE2: a new target for prevention of diabetic nephropathy?

A bundant, well-accepted evidence demonstrates a complete tissue renin-angiotensin system (RAS) within the kidney that plays many roles in the control of the intrarenal vasculature, as well in the control of glomerular and tubular processes (1). Substantial clinical and experimental data suggest that the intrarenal RAS is important, if not central, to the development and progression of diabetic nephropathy. Given the major impact of diabetic nephropathy on the health of diabetic individuals, to say nothing of health costs, alterations in the intrarenal RAS in diabetes have been of great interest, particularly given the demonstrated clinical benefit of blocking the RAS on the development and progression of diabetic nephropathy (2). However, although the presence of an intrarenal RAS is now well-accepted, the way we think about the RAS in health and disease changed with the discovery, in 2000, of ACE2, an angiotensin-converting enzyme (ACE)–related carboxypeptidase with approximately 40% homology with ACE (3,4). Before that time, some of the so-called “breakdown products” of angiotensin I and II [Ang I; Ang II] had unknown functions, and many in the field felt that these had little or no physiologic importance. However, now our understanding about processing and breakdown of angiotensins has changed. In thinking about prevention of diabetic nephropathy, we now must consider how ACE2 might be involved. ACE2, which preferentially removes carboxyterminal basic or hydrophobic acids, has as a major function the formation of the inactive angiotensin 1-9 from Ang I and the vasodilatory and antiproliferative angiotensin 1-7 from Ang II. In the six years since its discovery, it would appear that an overarching function of ACE2 is to counterbalance the effects of ACE, which forms Ang II (Figure 1) (5). We know that ACE2 is not responsive to ACE inhibitors (6), although we do not really know what stimulating ACE2 or inhibiting it will do clinically. The role of ACE2 in hypertension, diabetes, renal disease, and a number of other conditions is currently in the early phases of exploration. This editorial by Ingelfinger, which provides further perspective and insight into the potential clinical relevance of the description by Ye et al. of the localization of ACE2 expression in diabetic mice in JASN (pp. 3067– 3075), is also relevant to the article by Nobakhthaghighi et al. on the relationship between albuminuria and left ventricular mass in diabetes in this month’s issue of CJASN (pp. 1187–1190). ACE2 is an attractive new target for therapy to reduce albuminuria and cardiovascular complications in diabetes and other renal diseases.