흰쥐에서의 Cyclosporine-유발 신독성에 대한 Thromboxane A₂-수용체길항제, KT2-962, 의 효과 = Effects of Selective Thromboxane A₂Receptor Antagonist, KT2-962, on Cyclosporine-induced Nephrotoxicity in Rats
CsA is presently widely used for as a clincally proved immunosuppressive agents. Unfortunately, however, the therapeutic potential of this drug is often limited by accompanying nephrotoxicity. Various factors and effects have been hypothesized to explain the adverse effect of CsA on the renal function. However, the relative contrivutions of direct or indirect toxicity mediated through renal pathophysiology was related in part to renal vasoconctriction is multifactorial and unclear, but it has been suggested that TXA₂would be one of the important potential mediators of altered renal hemodynamics.
In this study, the efficacy of KT2-962(KT2). an azulene derivative of recently synthesized selective TXA₂receptor antagonist, in preventing acute nephrotoxicity in CsA-treated rats was examined and the elevations in urinaty N-acetly-β-D-glucosaminidase(NAG) activity along with BUN, serum creatinine levels, and creatinine clearance. Body weigh and urine outflow were also measured during experiment. Histological changes of the kidney was evaluated by electron microscopy. Male Wistar rats were administered CsA(25mg/kg, i.p) and/or KT2(30mg/kg, p.o) once daily for 20 consecutive days. The pretreament of extra KT2 for 3 days was given in coadministration of CsA+KT2.
The results (values are means±SE) obtained can be summarized as follows:
1) Urinary NAG Activity (U/mg of urine creatinine) :
It progressively increased to the maximal level, 153.7±11.7 on 14th day and then gradually decreased in the CsA group. KT2 coadministered with CsA, however, almost completely antagonized and normalized CsA-induced NAG activity elevations.
2) BUN Concentration (mg/dl):
Concentrations on 3rd weeks of treatment significantly increased in the CsA group (2.9 vs 28.9), but increment significantly inhibited to about 33% of values
3) Serum Creatinine Concentration (mg/dl):
It increased to 0.41±0.05 (0.37 vs 0.78) and 0.48±0.05(0.39 vs 0.86) in the KT2 and CsA group respectively on 3rd weeks of treatment. Serum creatinine concentration in the KT2+CsA
group were increased 0.39±0.05(0.40 vs 0.79) not significantly different from the CsA group
4) Creatinine Clearance (ml/min) :
It increased about 2.2 folds of pretreatment levels (0.42 vs 0.94) on 3rd weeks of treatment in the KT2 group, but decreased to 86% of control levels (0.43 vs 0.37) in the CsA group. In the KT2+CsA group, it significantly antagonized a decrease of creatinine clearance in the CsA group and increased about 2.4 folds of pretreatment levels(0.43 vs 1.02).
5) Urine Output (ml/20hrs) :
It slightly decreased in both KT2 and CsA groups, but a decrease of urine output was inhibited and increased significantly to about 2.3 folds of pretreatment value (7.8 vs 17.8) on 6th days of treatment in the KT2+CsA group.
6) Weigh Gain (gm):
Body weigh was progressively increased and gained about 36.0±2.3(254.0 vs 290.0) and 28.1±1.4 (280.4 vs 252.3) on 3rd weeks of treatment in the saline and KT2 group respectively. In contrast, there was 28.0±3.3 weight loss (253.1 vs 225.1) in the CsA group. KT2 coadministration with CsA ingibited weight loss with CsA alone and gained 23.5±1.0 (250.9 vs 274.4) in the KT2 CsA group.
7) In the electron microscopic finding of glomerulus ofthe CsA group, thickened basal lamina of capillary, irregular shaped pedicels of podocytes and indistinct slit pores are seen. Bowman's space are not seen. In epithelial cells of proximal convoluted tubule, large size oval vacuoles with dense debris and numerous phagocytes are distributed at apical portion of epihelial cell and in the middle portion of cell, nuclesus is deformed to irregular angular shape. The microvilli and mitochondria are industinct in shapes. But, In order groups, glomerulus and tubular epithelial cell are relatively preserved in normal apperances.
Consequently, it is suggested that endogenous TXA₂may paly an important role in CsA-induced nephrotoxicity and that coaministration of selective TXA₂receptor antagonist, KT2-962 can suppress CsA-nephrotoxicity in rats.
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