Vasopressin V2 receptors, ENaC, and sodium reabsorption: a risk factor for hypertension?

Abstract

Excessive sodium reabsorption by the kidney has long been known to participate in the pathogenesis of some forms of hypertension. In the kidney, the final control of NaCl reabsorption takes place in the distal nephron through the amiloride-sensitive epithelial sodium channel (ENaC). Liddle's syndrome, an inherited form of hypertension due to gain-of-function mutations in the genes coding for ENaC subunits, has demonstrated the key role of this channel in the sodium balance. Although aldosterone is classically thought to be the main hormone regulating ENaC activity, several studies in animal models and in humans highlight the important effect of vasopressin on ENaC regulation and sodium transport. This review summarizes the effect of vasopressin V2 receptor stimulation on ENaC activity and sodium excretion in vivo. Moreover, we report the experimental and clinical data demonstrating the role of renal ENaC in water conservation at the expense of a reduced ability to excrete sodium. Acute administration of the selective V2 receptor agonist dDAVP not only increases urine osmolality and reduces urine flow rate but also reduces sodium excretion in rats and humans. Chronic V2 receptor stimulation increases blood pressure in rats, and a significant correlation was found between blood pressure and urine concentration in healthy humans. This led us to discuss how excessive vasopressin-dependent ENaC stimulation could be a risk factor for sodium retention and resulting increase in blood pressure. water conservation; antidiuresis; sodium excretion; collecting duct VASOPRESSIN WAS FIRST IDENTIFIED as a pressor hormone and later recognized to be also a potent antidiuretic hormone. Today, these early historical discoveries have been explained by the identification of different receptor types. V1a receptors (V1aR), abundantly expressed in vascular smooth muscle cells, and signaling through calcium and phosphatidylinositol transducer pathways, are responsible for the pressor effects. V2 receptors (V2R), expressed mainly in principal cells of the renal collecting duct (CD), and signaling through cAMP, mediate the antidiuretic actions of the hormone (113).Vasopressin is elevated in some forms of human hypertension (26,92,111) and in animal models of hypertension (see reviews in Refs. 91 and 108). This hormone has long been suspected to play a role in blood pressure control because of its vasoconstrictive effects, well demonstrated in vitro. However, the studies trying to evaluate the contribution of V1aR-dependent effects in hypertension are inconclusive [either in favor of (27,35,70) or against (59, 98)].Excessive sodium reabsorption by the kidney is known to participate in the pathogenesis of some forms of hypertension.Among the genes responsible for monogenic forms of blood pressure disorders identified to date, the majority either mediate renal sodium transport in the distal part of the nephron or are involved in its regulation. Loss of function of the corresponding proteins leads to salt-wasting states with hypotension (48), ...

Vasopressin V1a and V1b Receptors: From Molecules to Physiological Systems

“…In fact, a pathological increase in serum AVP levels in the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) resulted in normal ranges of BP (353,392). However, in several experimental settings in rats and humans, V2 receptor stimulation by dDAVP or AVP increased not only water permeability but also sodium reabsorption, by directly promoting the activity of the sodium-potassiumchloride cotransporter (NKCC2) in the thick ascending limb of Henle's loop and the amiloride-sensitive epithelial sodium channel (ENaC) in the cortical collecting duct (38,39,404,442,443,505).…”

“…Although the physiological importance of V1a receptor-mediated natriuretic effects has not yet been determined, renal sodium metabolic control exerted by AVP is likely to result from a combination of opposite responses mediated by the V2 and V1a receptors (38). Luminal AVP has been shown to cause diuresis by inhibiting basolateral membrane V2 receptor-mediated water absorption and chloride conductance (367,375).…”

The physiological and pathophysiological functions of renal and extrarenal vasopressin V2 receptors

“…In addition, hormone binding of V2Rs stimulates ENaC activity and leads to an increase in Na ϩ transport in the thick ascending limb and collecting duct (4). AVP-induced Na ϩ retention due to ENaC activity has been suggested to be a risk factor for increases in blood pressure (3).…”

“…In contrast, V2R, which, uniquely among AVP receptor subtypes, signals through cAMP, has the key function of controlling fluid homeostasis. Its principal action is mediated through the AVP/V2R/aquaporin (AQP)2 system in medullary and cortical collecting ducts and other renal structures facilitating the urine concentrating mechanism and water, salt, and urea transport by modifying the trafficking of AQP2, epithelial Na ϩ channels (ENaC), and urea transporters (3,4,78). There are also V2Rs in the renal thick ascending limb of Henle, where they regulate NaCl transport and the countercurrent multiplication effects (42,44,80,103).…”

New insights into sodium transport regulation in the distal nephron: Role of G-protein coupled receptors

“…In the CCD, AVP activation of V2 elicits the phosphorylation of aquaporin-2 (AQP2) leading to its translocation to the apical membrane [22] . It also increases Na + reabsorption by activating ENaC [29,30] , as PKA phosphorylation leads to the inhibition of Nedd4-2, the ubiquitin ligase that promotes the endocytosis of ENaC [31,32] . Sodium reabsorption across the CD epithelium is essential for water absorption through aquaporins [33] .…”