Renal medullary endothelin-1 is decreased in Dahl salt-sensitive rats

Abstract

Although it is well established that the renal endothelin (ET-1) system plays an important role in regulating sodium excretion and blood pressure through activation of renal medullary ETB receptors, the role of this system in Dahl salt-sensitive (DS) hypertension is unclear. The purpose of this study was to determine whether the DS rat has abnormalities in the renal medullary endothelin system when maintained on a high sodium intake. The data indicate that Dahl saltresistant rats (DR) on a high-salt diet had a six-fold higher urinary endothelin excretion than in the DR rats with low Na ϩ intake (17.8 Ϯ 4 pg/day vs. 112 Ϯ 44 pg/day). In sharp contrast, urinary endothelin levels increased only twofold in DS rats in response to a high Na ϩ intake (13 Ϯ 2 pg/day vs. 29.8 Ϯ 5.5 pg/day). Medullary endothelin concentration in DS rats on a high-Na ϩ diet was also significantly lower than DR rats on a high-Na ϩ diet (31 Ϯ 2.8 pg/mg vs. 70.9 Ϯ 5 pg/mg). Furthermore, DS rats had a significant reduction in medullary ET B receptor expression compared with DR rats while on a high-Na ϩ diet. Finally, chronic infusion of ET-1 directly into the renal medulla blunted Dahl salt-sensitive hypertension. These data indicate that a decrease in medullary production of ET-1 in the DS rat could play an important role in the development of salt-sensitive hypertension observed in the DS rat.kidney; blood pressure; hypertension ENDOTHELIN-1 (ET-1) WAS FIRST characterized in 1988 as a potent vasoconstrictor released by endothelial cells (26). Two receptor subtypes have been since identified, ET A and ET B (24). Both of these receptors are located in the kidney with the highest concentration of ET B receptors existing within the medulla (11). Although the role of ET A receptors has been well characterized in the pathophysiology of experimental hypertension, the physiological importance of ET B receptors in modulating sodium excretion and blood pressure regulation in salt-sensitive hypertension is unclear. ET B activation inhibits sodium transport (15,18,19), and growing evidence suggests a critical role for the renal medullary endothelin system in the integrated response to a high-salt diet (6, 20 -21). For example, Pollock and others (4)have shown that renal ET-1 production is enhanced in response to 1 wk of a high-sodium diet, and intramedullary blockade of ET B receptors for 7 days leads to salt-sensitive hypertension. In addition, specific knockout of the ET B receptor gene and the ET-1 gene in the medullary collecting duct produces salt-sensitive hypertension (1, 6).Although there is growing evidence from a number of laboratories that the renal endothelin system via ET B receptor activation plays an important role in modulating renal pressure natriuresis and blood pressure regulation, very little is known about potential abnormalities in renal endothelin system in models of salt-sensitive hypertension. Our laboratory and others have reported that there is a rightward shift in the pressure natriuresis relationship in Dahl salt-sensitive r...

Oxidative Stress in Hypertension: Role of the Kidney

“…ET-1 production in the CD was increased by elevated Na + intake and associated with natriuresis (173). Paradoxically, medullary levels of ET-1 and ET B receptor expression were lower in DS rats than in DR rats on a high salt diet (269). However, renal expression of the ENaC was increased in DS rats (7) and this could represent a mechanism for the development of salt-sensitive hypertension.…”

“…Salt loading increased ET-1 production in the collecting duct (CD) of normal rats and mice (173). However, DS rats had lower medullary levels of ET-1 and endothelin receptor type-B (ET B ) receptor in response to a salt load than Dahl salt-resistant (DR) rats (269). Since ET-1 negatively regulates Na + reabsorption in the CD, the increased Na + transport at this site provides another potential pathway for salt-dependent renal oxidative stress.…”

Role of collecting duct endothelin in control of renal function and blood pressure

“…In addition, medullary ET-1 content is reduced in the renal papilla from Prague hypertensive rats compared with normotensive controls (100), whereas medullary ET-1 levels are lower in Dahl S compared with Dahl R rats (78). Dietary salt intake increased urinary ET-1 excretion in salt-resistant, but not salt-sensitive, hypertensive subjects (33), whereas reduced urinary ET-1 excretion has been reported in patients with essential hypertension (33,37,117).…”

Endothelin Receptor Antagonists (ERA) in Hypertension and Chronic Kidney Disease: a Rose with Many Thorns

“…In contrast, ET B receptor activation, apart from vasodilatation, inhibits sodium reabsorption in the renal collecting ducts [27]. ET B blockade causes salt-sensitive hypertension [28,29], and collecting duct ET-1 or ET B knockout mice exhibit blood pressure elevation and sodium retention [30,31].…”