Impaired sodium excretion, decreased glomerular filtration rate and elevated blood pressure in endothelin receptor type B deficient rats

Abstract

The renal endothelin (ET) system, particularly the ET type B receptor, has been implicated in the regulation of sodium excretion and glomerular filtration rate (GFR). We analyzed kidney morphology and function in a rat strain characterized by complete absence of a functional ETB receptor. Due to Hirschsprung's disease limiting lifetime in these rats, studies were performed in 23-day-old rats. Kidney size and morphology (glomerular and interstitial matrix content, glomerular size and cell density and intrarenal vascular morphology) were normal in ETB-deficient rats. There were also no evidence of altered kidney cell cycle regulation in these rats. GFR was significantly lower, by 72% (P<0.001), in homozygous ETB-deficient rats than in wild-type rats. Fractional sodium excretion was likewise markedly reduced by 84% in homozygous ETB-deficient rats (P<0.001 versus wild-type rats). Treatment with the specific epithelial sodium channel blocker amiloride led to a much higher increase in fractional sodium excretion in ETB-deficient rats (934.2+/-73% in ETB-deficient rats versus 297+/-20% in wild-type rats, expressed as percentage of corresponding placebo treated control; P<0.001). Mean arterial blood pressure was elevated by 7.9 mmHg in homozygous ETB-deficient rats (P<0.05 versus wild-type rats). Our study demonstrates that ETB-deficiency causes early onset kidney dysfunction characterized by a markedly reduced sodium excretion, decreased GFR, and slightly elevated blood pressure. The complete absence of the ETB receptor causes in the kidney--in contrast to the colon--a functional rather than a developmental, neural crest cell dependent disease, since kidney morphology was normal in ETB-deficient rats. The much higher increase in the fractional sodium excretion in ETB-deficient rats after pharmacological blockade of the epithelial sodium channel indicates that the decreased fractional sodium excretion in ETB-deficient rats is most probably due to a lack of the inhibitory property of the ETB receptor on the epithelial sodium channel activity.

Pattern of prepro-endothelin-1 expression revealed by reporter-gene activity in kidneys of erythropoietin-overexpressing mice

“…Another possible consequence of an activated tubular ET-system could be the promotion of natriuresis and diuresis in the renal tubule [15]. ET-1 inhibits the activity of the epithelial sodium channel via the ET B receptor, leading to a decrease in sodium and water re-absorption in the tubule system [16,17]. This could be a mechanism counteracting the elevated blood volume in Epo transgenic mice, thus reducing blood pressure [15,18,19].…”

ETA Receptor Blockade Induces Tubular Cell Proliferation and Cyst Growth in Rats with Polycystic Kidney Disease

“…Beside the effects on kidney fibrosis and cyst growth, the combined ETA/ETB receptor antagonist might have additional effects, via the ETB receptor, on renal water and salt excretion in ADPKD rats. It was recently shown that the complete absence of a functional ETB receptor in rats may cause salt-sensitive elevation of BP due to an enhanced tubular salt reuptake (16,34).…”

“…In vivo BrdU incorporation was performed exactly as recently described (16). Briefly, we injected BrdU intraperitoneally to label the DNA in vivo 24 h before scarifying the rats.…”

Endothelin ETBReceptors in Arteries and Veins: Multiple Actions in the Vein

“…Although there are no outstanding phenotypical changes in (D␤H)-ET B :ET B (sl/sl) rats that separate them from their D␤H-ET B :ET B (ϩ/ϩ) male littermates, blood pressure and circulating ET-1 concentrations are slightly elevated (Hocher et al, 2001). We do not believe this changed our in vitro results.…”