Orth S R, Odoni G, Amann K, Strzelczyk P, Raschack M, Ritz E
Department of Internal Medicine, Ruperto Carola University, Heidelberg, Germany.
J Am Soc Nephrol. 1999 Feb;10(2):387-91. doi: 10.1681/ASN.V102387.
The effect of the orally highly bioavailable and specific endothelin A (ET(A)) receptor antagonist LU 135252 was assessed in a model of chronic renal allograft nephropathy. Kidneys of Fisher rats were orthotopically grafted to Lewis rats. Fisher autografts and kidneys after uninephrectomy served as controls. All animals received low-dose cyclosporin A (CsA; 1.5 mg/kg body wt) for 10 d after surgery. Allotransplanted animals were then randomized to receive standard diet or a diet designed to deliver 30 mg of LU 135252/kg body wt per d for 35 wk. BP was monitored telemetrically. Treatment with LU 135252 did not affect systolic or diastolic pressure. Indices of glomerulosclerosis (GSI), and tubulointerstitial and vascular damage were measured. Chronic transplant nephropathy was almost completely prevented by LU 135252 compared with untreated allografts or kidneys of uninephrectomized controls, i.e., GSI 0.7 +/- 0.12 versus 1.6 +/- 0.25 (P < 0.001) versus 0.7 +/- 0.06 (P < 0.001). Allograft weight and serum creatinine were significantly lower in treated versus untreated animals. The results are consistent with the notion that ET(A) receptor-mediated events play a role in the genesis of chronic transplant nephropathy.
在慢性肾移植肾病模型中评估了口服生物利用度高且特异性的内皮素A（ET(A)）受体拮抗剂LU 135252的作用。将Fisher大鼠的肾脏原位移植到Lewis大鼠体内。Fisher自体移植肾和单侧肾切除后的肾脏作为对照。所有动物在术后10天接受低剂量环孢素A（CsA；1.5 mg/kg体重）。然后将同种异体移植动物随机分为接受标准饮食或设计为每天提供30 mg LU 135252/kg体重的饮食，持续35周。通过遥测监测血压。LU 135252治疗不影响收缩压或舒张压。测量肾小球硬化指数（GSI）以及肾小管间质和血管损伤指标。与未治疗的同种异体移植肾或单侧肾切除对照的肾脏相比，LU 135252几乎完全预防了慢性移植肾病，即GSI分别为0.7±0.12、1.6±0.25（P<0.001）和0.7±0.06（P<0.001）。与未治疗的动物相比，治疗动物的同种异体移植肾重量和血清肌酐显著降低。这些结果与ET(A)受体介导的事件在慢性移植肾病发生中起作用的观点一致。
