Impaired sodium excretion, decreased glomerular filtration rate and elevated blood pressure in endothelin receptor type B deficient rats.
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.
Hocher
B
B
Department of Nephrology, University Hospital Charité, Humboldt University of Berlin, Germany. berthold.hocher@rz.hu-berlin.de
Dembowski
C
C
Slowinski
T
T
Friese
S T
ST
Schwarz
A
A
Siren
A L
AL
Neumayer
H H
HH
Thöne-Reineke
C
C
Bauer
C
C
Nafz
B
B
Ehrenreich
H
H
D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D001158:Arteries / Q000502:physiology; D001794:Blood Pressure; D001973:Bromodeoxyuridine / Q000378:metabolism; D003404:Creatinine / Q000652:urine; D005838:Genotype; D005919:Glomerular Filtration Rate; D006720:Homozygote; D006973:Hypertension; D020287:In Situ Nick-End Labeling; D007668:Kidney / Q000473:pathology* / Q000502:physiology; D009929:Organ Size; D016133:Polymerase Chain Reaction; D051381:Rats; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000502:physiology*; D012964:Sodium / Q000652:urine*; D026941:Sodium Channel Blockers
D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D026941:Sodium Channel Blockers; D000584:Amiloride; D012964:Sodium; D003404:Creatinine; D001973:Bromodeoxyuridine