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ICV infusion of (pro)renin receptor antagonist (mPRO20) attenuates prorenin and DOCA‐salt induced hypertension (874.5)

We previously reported that the binding of prorenin to (pro)renin receptor (PRR) plays a major role in brain Ang II formation and development of deoxycorticosterone acetate (DOCA)‐salt hypertension. In this study, we designed and developed an antagonistic peptide (mPRO20) to block the binding of prorenin to PRR. Fluorescence‐labeled mPRO20 bound to both mouse and human brain tissue, and the dissociation constant was 14.5nM and 0.9nM respectively. The binding was blocked by co‐incubation with prorenin, indicating the specificity of mPRO20 to PRR. To test the in vivo effect of mPRO20, C57BL/6 mice were implanted with telemetric probes and intracerebroventricular (ICV) cannula. ICV infusion of mouse prorenin (300 ng in 3μl for 10 minutes) increased BP (ΔMAP: 28±3.4 mmHg); and this effect was attenuated by mPRO20 in a dose‐dependent manner (maximum effect, ΔMAP: 7±2.9 mmHg). Chronic ICV infusion of mPRO20 (40μg/kg/day, 21 days) attenuated the development of hypertension (113±3.3 vs. 134±3.6 mmHg, P<0.05), and the increase in brain Ang II levels (904±47 vs. 1371±88 pg/g) induced by DOCA‐salt. In addition, ICV infusion of mPRO20 improved autonomic function and spontaneous baroreflex sensitivity in mice treated with DOCA‐salt. In summary, mPRO20 binds to both mouse and human PRR, decreases Ang II formation and hypertension induced by either prorenin or DOCA‐salt. We conclude that mPRO20 may be a novel PRR antagonist for the treatment of hypertension.