Daniel Batlle
Northwestern University Feinberg University School of Medicine, USA
Title: ACE2 as a potential therapeutic agent for kidney disease
Biography
Biography: Daniel Batlle
Abstract
Angiotensin-converting enzyme 2 (ACE2) is a carboxypeptidase that potently degrades angiotensin II (Ang II) to form Ang-(1-7). Previous studies showed that injection of the enzymatic ectodomain of recombinant ACE2 (rACE2) markedly increasases circulatory levels of ACE2 activity, and effectively lowered blood pressure in Ang II-induced hypertension. However, due to the short plasma half-life of rACE2, its therapeutic potential for chronic use is limited. To circumvent this problem, we generated a chimeric fusion of rACE2 and the immunoglobulin fragment crystallizable (Fc) segment to increase its plasma stability. This rACE2-Fc fusion protein retained full peptidase activity and exhibited greatly extended plasma half-life in mice, from less than two hours of the original rACE2, to over a week. A single injection of 2 mg/kg rACE2-Fc elevated the overall Ang II-conversion activities in blood by up to 100 fold and lasted for over a week. Consequently, only rACE2-Fc, but not rACE2 injection, achieved sustained blood pressure control in response to a bolus infusion of Ang II. In the RenTgMK transgenic mice driven by the expression of synthetic renin cDNA, weekly injections of rACE2-Fc effectively lowered plasma Ang II and blood pressure. In addition the rACE2-Fc ameliorated albuminuria, and reduced kidney and lung fibrosis. These results show that this chimeric fusion strategy for rACE2-Fc can be suitable for future development of new RAS-based inhibition therapies.