Exaggerated vascular and renal pathology in endothelin-B-receptor-deficient rats with subtotal nephrectomy

The role of endothelin-B (ETB) receptor in partial ablation-induced chronic renal failure was evaluated using the spotting-lethal (sl) rat, which carries a naturally occurring deletion in the ETB receptor gene. After 5/6 nephrectomy in ETB-deficient homozygous and wild-type (+/+) rats, we measured the systolic blood pressure and renal functional parameters for 12 weeks. At the end of the experimental period, we collected an arterial blood sample and excised the remnant kidney, heart and aorta for biochemical measurements and histopathological studies. The ETBdeficient homozygous rats exhibited earlier and higher increases in systolic blood pressure, urinary protein excretion, blood urea nitrogen and plasma creatinine concentration, compared with cases in wild-type rats. Histopathologic examination of the kidney revealed glomerular and tubular lesions, alterations of which were more severe in homozygous than in wild-type rats. There was a significant increase in the renal endothelin-1 content in homozygous rats, but not in the wild-type rats. However, the aortic endothelin-1 contents were increased similarly in both groups. These results suggest that enhanced endothelin-1 production is at least partly responsible for the increased susceptibility to partial ablationinduced chronic renal failure in ETB receptor-deficient rats and that ETB receptor-mediated actions are protective against vascular and renal injuries in this disease.