Extrarenal ET _B Plays a Significant Role in Controlling Cardiovascular Responses to High Dietary Sodium in Rats

Abstract

Abstract-Endothelin-B receptor (ET B )-deficient rats have low-renin, salt-sensitive hypertension. We hypothesized this was caused by an absence of renal ET B signaling and performed a series of experiments to examine the effect of dietary sodium (Na) on endothelin-1 (ET1) expression and renal function in wild-type (WT) and ET B -deficient rats. We found that ET B deficiency, but not dietary Na, increases circulating and tissue (kidney and aorta) ET1 levels. Quantitative reverse-transcription polymerase chain reaction reveals that aortic and renal ET1 and endothelin-A receptor (ET A ) mRNA, however, are similarly increased by dietary Na in ET B -WT and ET B -deficient rats. We then determined the effect of chronic ET A blockade on blood pressure (direct conscious measurements), urinary protein excretion, and creatinine clearance (Crcl). On a Na-deficient diet, ET B -deficient rats have mild proteinuria and impaired Crcl. On a high-Na diet, severe hypertension and renal dysfunction develop in ET B -deficient rats. Chronic ET A blockade prevents hypertension and renal injury. To determine the role of the renal versus the extrarenal endothelin system, we performed renal cross-transplantation. We found that ET B deficiency in the body is associated with renal injury and an impaired ability to excrete an Na load. We also found that ET B deficiency in the body affects blood pressure response to dietary Na. Expression of ET1 and ET A are regulated by dietary Na. ET B receptors outside of the kidney, likely by functioning as a clearance receptor for ET1, limit salt-sensitivity in rats. Key Words: endothelin Ⅲ natriuresis Ⅲ proteinuria Ⅲ sympathetic nervous system Ⅲ transplantation T he endothelin-B (ET B ) receptor-deficient rat is a model of salt-sensitive hypertension resulting from a naturally occurring mutation in a single locus. These rats were created through the transgenic rescue of the spotting lethal (sl) rat. Spotting lethal is a 301-bp deletion in the ET B gene that abrogates functional receptor expression. 1 ET B sl/sl rats are rescued from their lethal intestinal phenotype via a dopamine-␤-hydroxylase (D␤H)-ET B transgene. D␤H-ET B ;ET B sl/sl rats express ET B in adrenergic tissues but fail to express ET B in other sites where they are normally expressed. [2][3][4] Although adult transgenic ET B wild-type (WT) (D␤H-ET B ;ET B ϩ/ϩ ) rats are not responsive to dietary sodium (Na), ET B -deficient (D␤H-ET B ;ET B sl/sl ) rats exhibit low-renin, amilorideresponsive, salt-sensitive hypertension. 4 The functional role of ET B in vascular homeostasis is controversial because it has both pressor and depressor effects. ET B activation on vascular smooth muscle mediates endothelin-1 (ET1)-induced vasoconstriction, whereas ET B activation on vascular endothelium produces a depressor response by evoking the production of the endotheliumderived vasodilators nitric oxide and/or prostacyclin. 5 ET B on the vascular endothelium also plays an important role in clearing circulating ET1, thereby reducing ET A -mediated press...

Collecting duct-specific knockout of the endothelin B receptor causes hypertension and sodium retention

“…Although not definitively studied, these concentrations suggest that the inhibitory effect of ET-1 is mediated by activation of ETB receptors (14). As discussed previously, whole animal knockout of the ETB receptor leads to amiloride-remediated salt-sensitive hypertension, although this cannot be primarily ascribed to the kidney (35). While no studies have examined the role of ETB receptors in mediating ET-1 inhibition of Na transport in isolated perfused CD, the ETB receptor has been demonstrated to mediate ET-1 inhibition of chloride flux in medullary thick ascending limb (40).…”

“…Rescued ETBdeficient rats have marked salt-sensitive hypertension that is partially normalized by amiloride, suggesting that the ETB receptor, by regulating the CD apical Na channel, is responsible for maintaining BP homeostasis (15). However, this same group reported that when normal kidneys were transplanted into ETB-deficient rats, BP remained elevated and sodium excretion was still impaired (35). Thus the salt-sensitive hypertension in genetically ETB receptor-deficient rats could not be ascribed wholly to renal ETB receptor absence.…”

The Endothelin System and Its Antagonism in Chronic Kidney Disease

“…These animals exhibit a sodium-dependent hypertension that is attributed to an absence of tonic inhibition of the epithelial sodium channel in the distal nephron (55). It is interesting that ET B receptor-deficient mice show renal injury, an impaired ability to excrete a sodium load, and hypertension that persists when they are cross-transplanted with wild-type kidneys, suggesting that it may be not only renal but also extrarenal ET B receptors that play a protective role against hypertension (75).…”

Attenuated vasoconstrictor responses to endothelin in afferent arterioles during a high-salt diet

“…In fact, the renal vasculature seems to be more sensitive to the vasoconstrictor effects of ET-1 than the systemic circulation (34). A HS diet has been shown to increase vascular expression of ET-1, although this is not a universal finding (20,26,29). We have previously observed that rats fed a HS diet for 2 wk had an increase in urinary excretion of immunoreactive endothelin by Ͼ250% (36).…”