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.
Highlights
The renin-angiotensin system (RAS) has long been established as the primary mechanism of hypertension through increased levels of angiotensin (Ang) II and its subsequent effects on sympathetic activity, arterial vasoconstriction, water reabsorption and sodium retention, among other actions [1]
Recent studies have provided evidence that angiotensin II (Ang II) is produced in the brain [6,7] and have established an important role for brain Ang II in the secretion of the pressor agent, arginine vasopressin (AVP); in addition to circulating levels of Ang II [5], brain Ang II is a contributor to hypertension
We previously reported that knockdown of the PRR in human renin and angiotensinogen double-transgenic (RA) mice contributes to a decrease in blood pressure(BP) in this Ang II-dependent hypertensive model [6]
Summary
The renin-angiotensin system (RAS) has long been established as the primary mechanism of hypertension through increased levels of angiotensin (Ang) II and its subsequent effects on sympathetic activity, arterial vasoconstriction, water reabsorption and sodium retention, among other actions [1]. Recent studies have provided evidence that Ang II is produced in the brain [6,7] and have established an important role for brain Ang II in the secretion of the pressor agent, arginine vasopressin (AVP); in addition to circulating levels of Ang II [5], brain Ang II is a contributor to hypertension. Renin is the rate limiting enzyme that cleaves angiotensinogen, initiating a cascade that leads to the production of Ang II and subsequent regulation of water and food intake [8], AVP secretion [9], and sympathetic activation [10]. The effects of the PRR on metabolic rate and body fluid homeostasis during hypertension have not been explored
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