Renal Endothelin in FK506-Induced Nephrotoxicity in Spontaneously Hypertensive Rats

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Abstract
FK506, a major immunosuppressive agent, often causes nephrotoxicity accompanied by renal vasoconstriction. It is recognized that endothelin (ET) plays a role in the cyclosporin A-induced nephrotoxicity, but the involvement of ET in the FK506-induced renal dysfunction is still poorly understood. We elicited nephrotoxicity by daily administration of FK506 in spontaneously hypertensive rats, and we examined the renal gene expression of ET and its receptors and the effects of an ET receptor antagonist on FK506-induced renal dysfunction. FK506 administration (4 mg/kg/day, i.m.) for 14 days induced nephrotoxicity, including a renal vasoconstriction and a decrease in glomerular filtration rate. The renal dysfunction was accompanied by an increase in ET-1 mRNA levels, while ETB-receptor mRNA was unaffected. Continuous administration of an ETA/ETB antagonist, TAK-044 (3 mg/day, s.c.), which effectively blocked systemic and renal vascular responses to exogenously administered ET-1, partially attenuated the FK506-induced renal vasoconstriction. However the reduced glomerular filtration rate were not affected by TAK-044. Thus, although enhanced gene expression of ET-1 in the kidney is involved in the renal vasoconstriction, ET does not play a major role in the FK506-induced renal dysfunction.