Chronic Activation of Vasopressin-2 Receptors Induces Hypertension in Liddle Mice by Promoting Sodium and Water Retention.

Overview

The renin-angiotensin-aldosterone and arginine vasopressin-V2 receptor-aquaporin-2 systems converge upon the epithelial sodium channel ENaC to regulate blood pressure and plasma tonicity. While it is established that V2 receptors initiate renal water reabsorption through aquaporin-2, whether V2 receptors can also induce renal sodium retention through ENaC and raise blood pressure remains an open question. We hypothesized that a specific increase in V2 receptor mediated ENaC activity can lead to high blood pressure. Our approach was to test effects of chronic activation of V2 receptors in Liddle mice, a genetic mouse model of high ENaC activity, and compare differences in ENaC activity, urine sodium excretion, and blood pressure with control mice. We found that ENaC activity was elevated in Liddle mice and could not be stimulated further by administration of dDAVP, a V2receptor specific agonist. In contrast, Liddle mice showed higher levels of expression of AQP2 and AQP3, but they could still respond to dDAVP infusion by increasing p-AQP2 expression. With dDAVP infusion, Liddle mice excreted smaller urine volume, less urine sodium, and developed higher blood pressure compared with control mice; this hypertension was attenuated with administration of the ENaC inhibitor benzamil. We conclude that V2 receptors contribute to hypertension in the Liddle mouse model by promoting primary sodium and concomitant water retention.