The (pro)renin receptor, which binds both renin and prorenin, is a newly discovered component of the renin angiotensin system that is highly expressed in the central nervous system. The significance of brain PRRs in mediating local angiotensin II formation and regulating blood pressure remains unclear. The current study was performed to test the hypothesis that PRR-mediated, non-proteolytic activation of prorenin is the main source of angiotensin II in the brain. Thus, PRR knockout in the brain is expected to prevent angiotensin II formation and development of deoxycorticosterone acetate salt induced hypertension. A neuron-specific PRR (ATP6AP2) knockout mouse model was generated using the Cre-LoxP system. Physiological parameters were recorded by telemetry. (Pro)renin receptor expression, detected by immunostaining and RT-PCR, was significantly decreased in the brains of knockout compared with wide-type mice. Intracerebroventricular infusion of mouse prorenin increased blood pressure and angiotensin II formation in wild type mice. This hypertensive response was abolished in (pro)renin receptor knockout mice in association with a reduction in angiotensin II levels. Deoxycorticosterone acetate salt increased (pro)renin receptor expression and angiotensin II formation in the brains of wild-type mice, an effect that was attenuated in (pro)renin receptor knockout mice. (Pro)renin receptor knockout in neurons prevented the development of Deoxycorticosterone acetate salt-induced hypertension as well as activation of cardiac and vasomotor sympathetic tone. In conclusion, non-proteolytic activation of prorenin through binding to the PRR mediates angiotensin II formation in the brain. Neuron-specific PRR knockout prevents the development of deoxycorticosterone acetate salt-induced hypertension, possibly through diminished angiotensin II formation.

We previously reported an anatomical connection from cardiovascular (CV)‐related brain nuclei to the bone marrow (BM) and an alteration of mesenchymal stem cell (MSC) colony‐forming ability during Ang II‐induced neurogenic hypertension. This study was conducted to determine if renin‐angiotensin system (RAS) components exist in BM‐related neurons, which will lay a foundation for study of the role of brain RAS in MSC regulation during hypertension. A retrograde pseudorabies virus (PRV) with a green fluorescent protein (GFP) tag was injected into the femoral bone marrow of mice (n=3). Six days post‐inoculation, mice were perfused with 4% paraformaldehyde and brains were harvested for immunostaining for GFP, angiotensin II type 1 receptor (AT1R), and (pro)renin receptor (PRR). PRR and AT1R were localized in BM‐related neurons in several CV regulatory brain regions, including the nucleus of the solitary tract, the rostral ventrolateral medulla, and most notably in the paraventricular nucleus (PVN) of the hypothalamus. The data suggests that key receptors of brain RAS are present in the BM‐related neurons and might play a role in the regulation of MSCs during the development of neurogenic hypertension.

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