Diabetic endothelin B receptor-deficient rats develop severe hypertension and progressive renal failure.
The endothelin (ET) system has been implicated in the pathogenesis of diabetic nephropathy. The role of the ET-B receptor (ETBR) is still unclear. The effect of ETBR deficiency on the progression of diabetic nephropathy in a streptozotocin model was analyzed in four groups: (1) Homozygous ETBR-deficient (ETBRd) diabetic rats, (2) ETBRd rats, (3) diabetic controls, and (4) wild-type controls. BP and kidney function were measured for 10 wk, followed by biochemical and histologic analysis of the kidneys. The study demonstrates that ETBRd diabetic rats on a normal-sodium diet develop severe hypertension, albuminuria, and a mild reduction of creatinine clearance. The strong BP rise seems not to be caused by activation of the renin-angiotensin-aldosterone system or by suppression of the nitric oxide system. Elevated plasma ET-1, possibly reflecting a reduced ETBR-dependent clearance, seems to cause the severe hypertension via the ETA receptor. The results do not support the hypothesis that a reduction of ETBR activity inhibits the progression of diabetic nephropathy. The study demonstrates for the first time that the combination of diabetes and ETBR deficiency causes severe low-renin hypertension with progressive renal failure.
Center for Cardiovascular Research/Institute of Pharmacology, Charité Mitte, Hessische Strasse 3-4, 10115 Berlin, Germany.
Thiemo
T
Pfab
Christa
C
Thöne-Reineke
Franziska
F
Theilig
Ines
I
Lange
Henning
H
Witt
Christiane
C
Maser-Gluth
Michael
M
Bader
Johannes-Peter
JP
Stasch
Patricia
P
Ruiz
Sebastian
S
Bachmann
Masashi
M
Yanagisawa
Berthold
B
Hocher
D000818:Animals; D001794:Blood Pressure; D003404:Creatinine / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000209:etiology*; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000097:blood; D006973:Hypertension / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D007676:Kidney Failure, Chronic / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology; D051381:Rats; D011922:Rats, Mutant Strains; D044022:Receptor, Endothelin A / Q000502:physiology; D044023:Receptor, Endothelin B / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
D019332:Endothelin-1; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D003404:Creatinine