Aldosterone-independent regulation of the epithelial Na ⁺ channel (ENaC) by vasopressin in adrenalectomized mice

Abstract

The epithelial Na + channel (ENaC) in the aldosterone-sensitive distal nephron (ASDN) is under negative-feedback regulation by the renin-angiotensin-aldosterone system in protection of sodium balance and blood pressure. We test here whether aldosterone is necessary and sufficient for ENaC expression and activity in the ASDN. Surprisingly, ENaC expression and activity are robust in adrenalectomized (Adx) mice. Exogenous mineralocorticoid increases ENaC activity equally well in control and Adx mice. Plasma [AVP] is significantly elevated in Adx vs. control mice. Vasopressin (AVP) stimulates ENaC. Inhibition of the V 2 AVP receptor represses ENaC activity in Adx mice. The absence of aldosterone combined with elevated AVP release compromises normal feedback regulation of ENaC in Adx mice in response to changes in sodium intake. These results demonstrate that aldosterone is sufficient but not necessary for ENaC activity in the ASDN. Aldosterone-independent stimulation by AVP shifts the role of ENaC in the ASDN from protecting Na + balance to promoting water reabsorption. This stimulation of ENaC likely contributes to the hyponatremia of adrenal insufficiency.epithelial transport | hypertension | sodium excretion | diabetes insipidus | sodium wasting R enal sodium excretion is fine-tuned in the aldosterone-sensitive distal nephron (ASDN). Here, the activity of the epithelial Na + channel (ENaC) is limiting for sodium reabsorption (reviewed in refs. 1 and 2). ENaC serves as the apical entry pathway for electrogenic Na + reabsorption through principal cells. Normal ENaC function is required for proper sodium balance and, thus, normal blood pressure. Gain-of-function mutations in ENaC cause inappropriate renal sodium retention and consequent increases in mean arterial pressure (2, 3). Inhibition of ENaC corrects the renal and blood pressure phenotypes resulting from such mutations. Loss-of-function mutations in ENaC, in contrast, cause renal sodium wasting and corresponding decreases in blood pressure (2, 4).The activity of ENaC is under negative-feedback regulation by the renin-angiotensin-aldosterone system (RAAS; ref. 1). The mineralocorticoid, aldosterone, is the final hormone in this cascade. This antinatriuretic factor is essential for proper Na + balance (5, 6). Decreases in blood pressure evoke via reninAngII signaling secretion of aldosterone from the adrenal gland. Aldosterone through the mineralocorticoid receptor (MR) stimulates ENaC in the ASDN to minimize renal sodium excretion in protection of Na + balance and vascular volume (2, 4). Pathological increases in aldosterone elevate blood pressure by promoting inappropriate renal sodium retention (7,8). Inhibition of ENaC ameliorates inappropriate renal sodium retention. In contrast, pathological decreases in aldosterone result in sodium wasting arising from inappropriate increases in renal sodium excretion (4,8,9). MR agonism and antagonism increase and decrease ENaC activity, respectively (10-12). There is strong support for a tight positive relation between...

Increased Renal Epithelial Na Channel Expression and Activity Correlate With Elevation of Blood Pressure in Spontaneously Hypertensive Rats

“…This negative feedback regulation has been well described recently, and ENaC expression appears to be robust in adrenalectomized mice where this aldosterone independent stimulation became modulated by arginine vasopressin. 17 To evaluate in vivo ENaC expression, we measure its activity in perfused kidneys by determining 22 Na uptake in the presence of inhibitors of Na + /H + exchange (ethylisopropylamiloride), Na + , K + , 2Cl − cotransport (bumetanide) and Na + , Cl − cotransport (hydrochlorothiazide; ie, major ion carriers providing Na transport across apical membranes in proximal tubules, thick ascending limb, and distal tubules, respectively). Figure 6 shows that both β-and γ-ENaC expression and 22 Na uptake were increased by ≈40% in 65-to 77-weekold SHR compared with young rats of the same strain without any age-dependent increment in normotensive WKY controls.…”

“…[40][41][42] More recently, Karpushev et al 43 reported that WASP proteins increased ENaC activity when coexpressed in Chinese hamster ovary cells. The role of Fnbp1 in cytoskeleton-and WASP-mediated regulation of ENaC activity and involvement of aldosterone-independent regulation by vasopressin 17 are currently investigated in our laboratory.…”

Novel Criteria of Urine Osmolality Effectively Predict Response to Tolvaptan in Decompensated Heart Failure Patients

“…30 Inhibition of the V2 receptor by TLV may repress ENaC activity in the distal nephrons and result in increased sodium excretion. 31 Finally, we emphasize 2 advantages of the new criteria. These are the first-ever reported predictors of TLV efficacy, and could successfully stratify responders/non-responders to TLV.…”

Renal neurohormonal regulation in heart failure decompensation

“…Vasopressin regulates water reabsorption through the V2 receptor by affecting aquaporin 2 translocation, an important mechanism for fluid retention in heart failure (3,60). Vasopressin further stimulates sodium reabsorption by stimulating epithelial Na ϩ channel in the distal nephron (44), potentially through oxytocin receptors (58). Urea transport through the urea transporter A is important for the concentrating ability by regulating the medullary concentration gradient (14) and is regulated by vasopressin (13), but little is known about the regulation of urea transport in heart failure.…”