Junji Uchida (1), Katsuyuki Miura (1,2,*), Shinya Yamanaka (2), Shokei
Kim (2), Hiroshi Iwao (2), Tatsuya Nakatani (1) and Taketoshi Kishimoto
(1)
(1) Department of Urology and (2) Department of Pharmacology, Osaka City
University Medical School, 1-4-54 Asahimachi, Abeno, Osaka 545, Japan
(*) To whom correspondence should be addressed (2).
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.
Keywords: FK506, Endothelin, Nephrotoxicity, TAK-044, Spontaneously hypertensive
rats