Deletion of Prorenin Receptor in the Rostral Ventrolateral Medulla Results in Biphasic and Sex-Dependent Pressor Responses in Deoxycorticosterone Acetate-salt Hypertension.

In models of low renin hypertension such as the deoxycorticosterone acetate (DOCA)-salt model, the local generation of angiotensin II in the brain mediates the increase in blood pressure. The prorenin receptor (PRR) might play a potential role in the local activation of prorenin in the brain. We have new evidence that prorenin and PRR are co-expressed in the proximity to the rostral ventrolateral region of the medulla oblongata (RVL). Therefore, we hypothesized that selective ablation of PRR targeting the RVL attenuates responses to DOCA-salt in mice. PRR ablation was targeted to the RVL by stereotactic microinjections of adeno-associated virus (AAV) expressing Cre recombinase in PRR-flox mice (PRRRVL-KO ). AAV mCherry was used as a control virus (WT). Pressor response to L-glutamate in the injection site served as confirmatory stereotactic target hit. During the first week of DOCA-salt treatment, RVL-targeted ablation of PRR resulted in lower pressor responses to DOCA-salt in females (WT=115±3 vs KO=104±4 mmHg; p<0.05; n=8), but not males. However, after week 2 on DOCA-salt treatment, female PRRRVL-KO unexpectedly exhibited an exaggerated increase in systolic blood pressure (WT=149±3 vs KO=163±3 mmHg; p=0.004; n=8) and this was accompanied by a trending increase in urinary norepinephrine (WT=177±28 vs KO=270±38 ng/ml; p=0.07; n=7-8). Next, female mice were challenged with an intraperitoneal hypertonic saline injection equivalent to 10% of their body weight followed by 4 hours of urine collection at baseline and on DOCA-salt treatment. Urinary sodium excretion in female PRRRVL-KO was significantly lower when compared to WT in both conditions (p<0.05). Finally, using nuclear magnetic resonance/bioimpedance spectroscopy we assessed body fluid compartmentalization. We observed no difference in total body fluid among groups at any time point, but there was a significant mobilization of extracellular fluid to the intracellular compartment in PRRRVL-KO . Our data indicate that the role of PRR in the RVL is sex-dependent and biphasic. That is, PRR contributes to the pressor response during the initial stage of DOCA-salt hypertension in females, presumably by facilitating the generation of angiotensin peptides in the RVL, while it plays a protective role by promoting renal sodium excretion and preventing blood pressure elevation during the maintenance stage of DOCA-salt hypertension. This study also suggests that distinct PRR expressing cell populations within the RVL might elicit diverging physiological functions.