ACE2 Amplification, Unlike ACE Inhibition, Does Not Suppress Plasma Aldosterone: Implications for Hyperkalemia

Background: Hyperkalemia is a complication of renin angiotensin system (RAS) blockers, such as ACE inhibitors and Angiotensin II Type 1 receptor blockers. The increase in plasma K+ is caused primarily by suppression of angiotensin (Ang) II-driven stimulation of aldosterone secretion by the adrenal glands. Angiotensin Converting Enzyme 2 (ACE2) is an enzyme that metabolizes Ang II thereby downregulating the RAS downstream of Ang II. We hypothesized that downregulation of the RAS by administering ACE2 should not suppress aldosterone. Methods: A shorter form of soluble ACE2 with extended duration of action bioengineered in our lab (ACE2 618ABD) was administered S.C. (2 mg/kg) to wild-type C57bl6 mice every 2-3 days for one week. Its effect on plasma aldosterone was compared to the administration of the ACE inhibitor, captopril (60 mg/kg/d in drinking water), also for one week. Plasma aldosterone and angiotensin I were measured by ELISA. Results: Captopril resulted in the expected decrease in plasma aldosterone (from 269 ± 57 to 97 ± 41 pg/ml, p=0.03) whereas ACE2 618 ABD did not (from 244 ± 30 to 330 ± 56 pg/ml, p=0.24). Therefore, aldosterone was significantly lower with captopril than with ACE2 618 ABD (Figure1A). ACE2 618ABD administration resulted in a large increase in plasma ACE2 activity whereas captopril did not (286 ± 15 vs 3 ± 6.9 RFU/ul/hr, p<0.0001). Blockade of Ang II formation with captopril resulted a marked increase in Ang I which was not observed with ACE2 618 ABD (Figure 1B). Conclusion: Downregulation of RAS using a shorter form of soluble ACE2, unlike blocking the formation of Ang II using an ACE inhibitor, does not reduce plasma aldosterone. This attribute of ACE2618ABD should represent a potentially important advance by eliminating the risk of hyperkalemia in patients with CKD and heart failure in need of RAS downregulation. Funding: NIDDK Support