흰쥐에서 부분적 실절제로 유발된 단백뇨와 진행성 신병변에 대한 Thromboxane A₂-수용체 길항제 KT2-962의 효과 = Effects of the thromboxane A₂receptor antagonist KT2-962 on the proteinuria and progressive renal failure resulting from subtotal nephrectomy in rats.

다국어 초록 (Multilingual Abstract)

Animal experiments implicate renal synthesis of the vasodilator prostacyclin and the vasoconstrictor thromboxane(TX) A₂in renal damage and show that renal TXA₂mediates the glomerular permeability to protein associated with immunological or toxic damage to the glomerulus and synthesized significantly more TXA₂than normal rats. A specific pharmacologic approach, designed to prevent such pathologic sequelae, is to antagonize selectively the thrombotic and vasospastic activities of TXA₂using a specific TXA₂antagonist.
The aims of the present study were to assess the effect of KT2-962, a recently developed specific TXA₂receptor antagonist derived from azulene derivatives, on pathologic sequelae following subtotal(3/4) nephrectomy and body weight, 24hrurine output, 24hr-urine protein excretion at 4 days interval, and blood urea nitrogen(BUN) and serum creatinine levels just prior to surgery and at the end of experiment were measured. Rats were killed at the end of experimental period, 40 days after nephrectomy and histological changes were evaluated by electron microscope. 20 rats were divided into a control (non treated) and a KT2-962 treated groups. The effect of KT2-962 was observed by daily oral administration at 30 mg/kg in saline solution from 5 days before to 40 days after the subtotal nephrectomy.
The results obtained can be summarized as follows:
1)Body weight were decreased gradually to 88.2% of initial on 12 days after nephrectomy, and thereafter tended to increase progressively, but it was still less than prior to nephrectomy, 96.5%, for nontreated group. In KT2-962 treated group, lesser decrement in body weight was continued until 16 days after nephrectomy and thereafter gradually increased to near or even higher than weight at preoperative period after 38 days of nephrectomy.
2)24hr-urine output followed immediately after subtotal nephrectomy andconsistantly continued during experimental period for controls, However, urine output were increased slightly during experimental period for KT2-962 treated group.
3)Urinary protein excretion was consistantly increased during experimental period and amount of protein in 24 hours-urine(mean±SE) reached to maximum, 148.6±3.5mg/day which is 2.2 folds of preoperative levels at the end of experiment, 40 days after nephrectomy, for control. In KT2-962 treated group, increased urinary protein excretion was ingibit, although reached maximally to 104.3±6.7mg/day on 24 days after nephrectomy, corresponding 1.6 times of preoperative level which is about 70% of maximum in nontreated group, and thereafter decreased gradually to 78.9±6.8gm/day, corresponding 1.2 folds of initial, on 40 days after nephrectomy.
4)BUN were elevated to 4.2 times of preoperative levels on 40 days after nephrectomy for control, but to 2.1 times for KT2-962 treated group. The serum creatinine were increased to 2.4 times of preoperative levels on 40 days after nephrectomy for control, but to 2.1 times for KT2-962 treated group.
5)In electron microscopic findings of nontreated rat glomerulus, Pedicels of the podocytes are regularly distributed on the basal lamina. The basal lamina showed irregular electron dense central lines and isn't homogenous. The endothelial cell of capillary revelaed irregular fenestrated pores. The bowman's space is wide. In KT2-962 treated rat glomerulus, the fenestration of endothelial cell in capillary are clearly seen in normal state. Homogenous basal lamina and regularly arranged pedicels of podocyte with clear slit pores are well observed and intact endothelial c3ell and Bowman's space is normally observed.
Consequently, it is suggested that endogenous TXA₂may be a important role in proteinuria and a progressive renal failure resulting from partial nephrectomy in rats and chronic oral administration of KT2-962, TXA₂/PGH₂-receptor antagonist, in rat with remnant kidney is expected to ingibit proteinuria and progressive renal failure.