Reduced plasma ACE2 activity in dialysis patients: another piece in the conundrum of factors involved in hypertension and cardiovascular morbidity?

The renin–angiotensin system (RAS) is a complex regulatory network consisting of enzymes and effector peptides that facilitate the maintenance of homeostasis of several physiological processes [1, 2]. Upregulation of the RAS system, however, under chronic conditions and mainly through the interactions of Ang II with the AT1 receptor, can lead to hypertension and is involved in the progression of diabetic and nondiabetic chronic kidney disease (CKD) [2, 3]. Clinical interventions targeting the RAS and its pathogenic actions have been centered on the use of RAS blockers [3]. More recently, it has been proposed that the RAS system could be therapeutically targeted by increasing Ang II degradation and Ang (1–7) formation via ACE2 enzyme activation [2, 4–7]. ACE2, a monocarboxypeptidase discovered in 2000, metabolizes Ang II by removing a single amino acid, phenylalanine, from the C-terminus of this peptide [8], which results in the formation of Ang-(1–7) [8, 9]. Angiotensin-(1–7) has anti-inflammatory and antiproliferative actions that tend to counteract the proinflammatory and pro-proliferative effects of Ang II. ACE2 is a type-1 integral membrane glycoprotein [10] that is expressed largely in the kidney, and the intestine, but is also present in the heart, lungs and brain and is more ubiquitous than initially thought [2]. In its full-length form, ACE2 consists of three structural entities: the cytosolic, transmembrane and extracellular domains and has a molecular weight of 120– 130 kD [11–15]. The extracellular domain of ACE2, which confers its enzymatic activity, contains a single catalytic metallopeptidase unit that shares 42% sequence identity and 61% sequence similarity with the catalytic domain of ACE [8]. Notably, pharmacologic ACE inhibitors used in clinical practice do not inhibit ACE2 [8]. In this issue of Nephrology Dialysis Transplantation, Roberts et al. [16] showed that among patients with CKD plasma ACE2 activity is lower in those undergoing hemodialysis for end stage renal disease (ESRD) when compared with predialysis patients with CKD or renal transplant patients. When compared with historic samples from healthy subjects, however, all CKD groups examined, i.e. predialysis, transplant patients and even subjects on dialysis, seemed to have increased levels of plasma ACE2 activity. Statistical comparisons with healthy controls, however, could not be done because samples from healthy individuals were not assayed concurrently with those in the present study. What the study shows, in our opinion, is that while plasma ACE2 activity tends to increase in CKD patients, perhaps as a compensatory mechanism to attenuate Ang II overactivity, at the time that ESRD is reached and dialysis initiated a relative deficiency in plasma ACE2 activity ensues. What is then the significance of reduced plasma ACE2 activity in dialysis patients? As ACE2 is mainly involved with the degradation of Ang II, one could readily speculate that the levels of this peptide could be augmented thereby predisposing to hypertension and other cardiovascular morbidity. As the levels of Ang II or Ang (1–7) were not measured in this study, one can only consider this as a predictable consequence of ACE2 deficiency that, however, still needs to be demonstrated. One also wonders about the significance of plasma ACE2 activity since ACE2 is mainly a tissue enzyme and its levels in the circulation, unlike the levels of ACE, are relatively low. Initial attempts to measure ACE2 directly in plasma from healthy individuals were unsuccessful [17, 18]. Moreover, circulating ACE2 enzymatic activity has also been shown to be low or even undetectable in animals under physiological conditions [19–22]. Interestingly, in pathological states in humans, such as ischemic heart disease [23], heart failure [24] and diabetes accompanied by vascular complications [25] as well as in rodent models of diabetes [19, 26] circulating ACE2 activity is augmented. Other studies in patients with connective tissue diseases, by contrast, have reported antibodies against plasma ACE2 that reduce enzymatic activity [27]. IN F O C U S