The (pro)renin receptor is a newly discovered member of the brain renin-angiotensin system. To investigate the role of brain (pro)renin receptor in hypertension, adeno-associated virus-mediated (pro)renin receptor shRNA was used to knockdown (pro)renin receptor expression in the brain of non-transgenic normotensive and human renin-angiotensinogen double transgenic hypertensive mice. Blood pressure was monitored using implanted telemetric probes in conscious animals. Real-time PCR and immunostaining were performed to determine (pro)renin receptor, angiotensin II type 1 receptor and vasopressin mRNA levels. Plasma vasopressin levels were determined by Enzyme-Linked Immuno Sorbent Assay. Double transgenic mice exhibited higher blood pressure, elevated cardiac and vascular sympathetic tone, and impaired spontaneous baroreflex sensitivity. Intracerebroventricular delivery of (pro)renin receptor shRNA significantly reduced blood pressure, cardiac and vasomotor sympathetic tone, and improved baroreflex sensitivity compared to the control virus treatment in double transgenic mice. (Pro)renin receptor knockdown significantly reduced angiotensin II type 1 receptor and vasopressin levels in double transgenic mice. These data indicate that (pro)renin receptor knockdown in the brain attenuates angiotensin II-dependent hypertension and is associated with a decrease insympathetic tone and an improvement of the baroreflex sensitivity. In addition, brain-targeted (pro)renin receptor knockdown is associated with down-regulation of angiotensin II type 1 receptor and vasopressin levels. We conclude that central (pro)renin receptor contributes to the pathogenesis of hypertension in human renin-angiotensinogen transgenic mice.

The renin-angiotensin system (RAS) has long been established as one of the major mechanisms of hypertension through the increased levels of angiotensin (ANG) II and its resulting effect on the sympathetic nerve activity, arterial vasoconstriction, water reabsorption, and retention, etc. In the central nervous system, RAS activation affects body fluid homeostasis through increases in sympathetic nerve activity, water intake, food intake, and arginine vasopressin secretion. Previous studies, however, have shown that ANG II can be made in the brain, and it could possibly be through a new component called the (pro)renin receptor. This review intends to summarize the central and peripheral effects of the PRR on body fluid homeostasis.

Objectives: The (pro) renin receptor (PRR) is highly expressed in the brain and is involved in the central regulation of blood pressure. However, the role of the brain PRR in regulating body fluid homeostasis in hypertension remains unclear. We hypothesized that the brain PRR knockdown modulates water intake, urine, and urinary sodium excretion in the context of angiotensin II (Ang II)-induced hypertension. Methods and Results: Brain PRR was knocked down in non-transgenic (NT) normotensive and human reninangiotensinogen double-transgenic (RA) mice by intracerebroventricular (ICV) injection of adeno-associated virus expressing short hairpin RNA targeting the PRR (AAV-PRR-shRNA). Water and food intake, and urinary excretion were recorded using metabolic cages. At baseline, RA mice exhibited higher water intake, food intake, urine excretion, urinary sodium excretion and potassium excretion compared to NT mice. PRR knockdown in the brain significantly decreased water and food intake, and urinary potassium and sodium excretion in RA mice, but had no such effects in NT mice. PRR knock down also decreased reactive oxygen species generation and plasma Ang II concentration in RA mice. Conclusion: PRR knockdown modulates body fluid homeostasis in hypertensive RA mice, suggesting that the brain PRR plays a role in regulating body fluid homeostasis during Ang II-dependent hypertension.

We previously reported that brain‐targeted PRR knockdown attenuates Angiotensin (Ang) II‐dependent hypertension and decreases vasopressin (AVP) release. To address the role of PRR in body fluid homeostasis, adeno‐associated virus‐mediated PRR shRNA (AAV‐PRR‐shRNA) was intracerebroventricularly injected to non‐transgenic (NT, n = 5) and human renin and angiotensinogen transgenic (RA, n= 6) mice. Urine excretion and water intake were recorded using metabolic cages. Ang II levels were measured at baseline and two weeks after PRR knockdown. At baseline, RA mice exhibited higher water intake (5 ± 0.6 VS. 3 ± 0.5 mL/day, p< 0.05), urine excretion (3.3 ± 0.5 VS 1.9 ± 0.1mL/day, p< 0.05), and urinary sodium excretion (0.3 ± 0.1 VS. 0.1 ± 0.1mmol/day, p< 0.05) compared to NT mice. PRR knockdown decreased water intake (3.3 ± 0.6 mL/day, p< 0.05) and urinary sodium excretion (0.2 ± 0.1mmol/day, p< 0.05) in RA mice. In addition, PRR‐shRNA significantly decreased Ang II levels in both the hypothalamus (1470 ± 90 VS. 1051 ± 77 fmol/mg, p< 0.05) and plasma (347 ± 41 VS. 156 ± 42 fmol/ml, p< 0.05) compared to baseline in RA mice; however, it did not alter Ang II levels in NT mice. This data indicates that brain‐targeted PRR knockdown modulates the body fluid homeostasis and is associated with reduction of Ang II levels, and brain PRR plays a regulatory role in the body fluid homeostasis during Ang IIdependent hypertension.

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