Loss of renal medullary endothelin B receptor function during salt deprivation is regulated by angiotensin II

Abstract

Kittikulsuth W, Pollock JS, Pollock DM. Loss of renal medullary endothelin B receptor function during salt deprivation is regulated by angiotensin II. Am J Physiol Renal Physiol 303: F659 -F666, 2012. First published June 6, 2012 doi:10.1152/ajprenal.00213.2012.-We have recently demonstrated that chronic infusion of exogenous ANG II, which induces blood pressure elevation, attenuates renal medullary endothelin B (ETB) receptor function in rats. Moreover, this was associated with a reduction of ET B receptor expression in the renal inner medulla. The aim of this present work was to investigate the effect of a physiological increase in endogenous ANG II (low-salt diet) on the renal ET system, including ET B receptor function. We hypothesized that endogenous ANG II reduces renal medullary ET B receptor function during low-salt intake. Rats were placed on a low-salt diet (0.01-0.02% NaCl) for 2 wk to allow an increase in endogenous ANG II. In rats on normal-salt chow, the stimulation of renal medullary ET B receptor by ETB receptor agonist sarafotoxin 6c (S6c) causes an increase in water (3.6 Ϯ 0.4 from baseline vs. 10.5 Ϯ 1.3 l/min following S6c infusion; P Ͻ 0.05) and sodium excretion (0.38 Ϯ 0.06 vs. 1.23 Ϯ 0.17 mol/min; P Ͻ 0.05). The low-salt diet reduced the ET B-dependent diuresis (4.5 Ϯ 0.5 vs. 6.1 Ϯ 0.9 l/min) and natriuresis (0.40 Ϯ 0.11 vs. 0.46 Ϯ 0.12 mol/min) in response to acute intramedullary infusion of S6c. Chronic treatment with candesartan restored renal medullary ET B receptor function; urine flow was 7.1 Ϯ 0.9 vs. 15.9 Ϯ 1.7 l/min (P Ͻ 0.05), and sodium excretion was 0.4 Ϯ 0.1 vs. 1.1 Ϯ 0.1 mol/min (P Ͻ 0.05) before and after intramedullary S6c infusion, respectively. Receptor binding assays determined that the sodium-depleted diet resulted in a similar level of ET B receptor binding in renal inner medulla compared with rats on a normal-salt diet. Candesartan reduced renal inner medullary ET B receptor binding (1,414 Ϯ 95 vs. 862 Ϯ 50 fmol/mg; P Ͻ 0.05). We conclude that endogenous ANG II attenuates renal medullary ET B receptor function to conserve sodium during salt deprivation independently of receptor expression. low-salt diet; ETB receptor; renal medulla; renin-angiotensin system; natriuresis THE ENDOTHELIN (ET) and renin-angiotensin system (RAS) play an important role in sodium balance and blood pressure control. ET-1 is highly produced in the kidney, especially by the inner medullary collecting duct (23). ET-1 via ET B receptor activation in the renal medulla stimulates nitric oxide production to facilitate water and sodium excretion (27) via increased renal medullary blood flow (43) and inhibition of epithelial sodium channel activity (ENaC) (8, 9) as well as reabsorption in the medullary thick ascending limb (30). In contrast, ANG II prominently acts as an antinatriuretic hormone at least in part by increasing abundance of sodium transporters and channels along the nephron, mainly mediated by the AT 1 receptordependent pathway (22). Differences in salt intake affect both the ET system ...

Blood pressure and amiloride-sensitive sodium channels in vascular and renal cells

“…179 Medullary endothelin B receptor activation is associated with increased renal Na + excretion, an effect that is blunted by Angiotensin II. 180 Impaired salt excretion would thus occur in the setting of over-activity of the renin-angiotensin-aldosterone system, and an imbalance between endothelin A and endothelin B receptor activation. Salt-sensitive hypertension is associated with impaired sodium excretion and inflammatory infiltrates in the tubulo-interstitium.…”

New Clues Towards Solving the Mystery of Endothelin and Blood Pressure Regulation

“…These findings emphasize the idea that maintaining a balance between ET A and ET B receptor function is key to maintain proper physiologic function, and that receptor imbalance, not elevated ET-1 per se, may be the key initiator of pathophysiological situations such as hypertension. Along these lines, our laboratory has reported evidence for angiotensin II dependent down-regulation of the renal ET B receptor, 8 which could account for salt-sensitivity in this model as well as the observations that ET A blockade can counteract the hypertensive effects of angiotensin II.…”

High salt intake increases endothelin B receptor function in the renal medulla of rats

“…Rats on both normal and high salt diets were divided into three groups in which either normal saline (time control), low dose S6c (0.15 μg/kg/hr, in saline), or ET-1 (0.45 μg/kg/hr, in saline) was infused into the medullary interstitium during the experimental periods. We previously reported that S6c produced a significant natriuresis in rats on a NS diet at a dose of 0.45 μg/kg/hr, but lower doses were less effective (Kittikulsuth et al, 2011, 2012, Nakano et al, 2008). Since we expected to see a more robust natriuresis, we used a lower dose of S6c.…”