Brain-Targeted (Pro) Renin Receptor Knockdown Modulates Body Fluid Homeostasis

Abstract

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.