Abstract Body: BACKGROUND. With RAS blockers, plasma renin increases markedly, which is an undesirable effect because renin overactivity continues to form Ang I from angiotensinogen and, in addition, has profibrotic actions through Ang II-independent mechanisms. Also of great concern is the recent finding that long-term use of RAS blockers results in transformation of renin producing cells to a matrix secretory phenotype with the development of vascular hypertrophy of renal arterioles. We hypothesize that downregulation of RAS downstream of Ang II via ACE2 amplification should not result in a reactive increase in plasma renin.

METHODS. A shorter form of human ACE2 with extended duration of action termed hACE2 618ABD bioengineered in our lab was administered s.c. (2 mg/kg), to wild type mice (C57bl6) every 2- 3 days for a week and its effect on plasma renin compared to the administration of the ACE inhibitor, captopril (60mg/kg), also for a week. Plasma renin and angiotensin I were measured by ELISA.

RESULTS. Captopril resulted in the expected increase in plasma renin (from 240 ± 16 to 2443 ± 326 pg/ml, p<0.001) whereas hACE2 618ABD did not increase it significantly (from 238 ± 23 to 345 ± 34 pg/ml, p=0.87) (Figure 1A). Blockade of Ang II formation with captopril resulted in the expected increase in Ang I (from 757 ± 219 to 2482 ± 257 pg/ml, p<0.001) whereas enhancing its degradation with hACE2 618ABD did not (from 613 ± 127 to 890 ± 232 pg/ml, p=0.63) (Figure 1B). In mice treated via hACE2 618ABD, plasma ACE2 activity was markedly increased compared to captopril treated mice (286 ± 15 vs 3 ± 7 RFU/ul/hr, p<0.0001).

CONCLUSION. Downregulation of RAS using a novel soluble ACE2 recombinant protein, unlike blocking the formation of Ang II using an ACE inhibitor, did not cause an increase in plasma renin. This differential attribute of hACE2 618ABD represents a potential therapeutic advantage by avoiding undesirable actions of excess renin, including the need for sustained plasma renin levels by renin producing cells and the risk of unwanted vascular hypertrophy.