内皮素-1在环孢素A慢性肾毒性中的作用的研究

Studies on the funtion of endothelin-1 in rat model of chronic nephrotoxicity of cyclosporine A

目的探讨内皮素-1(ET-1)在环孢素A(CsA)慢性肾毒性大鼠模型中的作用。方法将实验动物分为CsA(橄榄油)对照组A组,CsA10 mg/(kg.d)B组,CsA15 mg/(kg.d)C组,CsA20 mg/(kg.d)D组,皮下注射4周,每天根据大鼠的体重变化调整CsA用量,4周后检测大鼠静脉血中肌酐、CsA、ET-1的含量。用放射免疫法检测各组大鼠模型肾皮质、髓质中ET-1的含量并研究ET-1在CsA慢性肾毒性中的作用。结果小剂量CsA即可以引起血清肌酐升高,剂量增大后Scr未见明显上升,提示CsA慢性肾毒性与药物剂量和血药浓度无明显关系,处理组血浆中ET-1浓度较对照组A组无显著性差异(P>0.05)。局部肾组织中皮质、髓质ET-1的含量增加(高剂量D组髓质除外),提示ET-1主要以局部自分泌和旁分泌在CsA慢性肾毒性起重要作用。血循环中ET-1对CsA慢性肾毒性影响不大,高剂量组髓质的ET-1含量减少,可能与肾小管萎缩后失去分泌生物活性物质功能有关。

Objective：To explore the effects of endothelin-1 on chronic nephrotoxicity of cyclosprine A in rat model.Methods： The Wistar rats were randomly divided into 4 groups： control group（Group A,n=8）,CsA 10mg/（kg.d）（Group B,n=8）,CsA 15mg/（kg.d）（Group C,n=8）,CsA 20mg/（kg.d）（GroupD,n=8）.The rats were injected subcutaneously for 4 weeks consecutively to develop chronic nephrotoxicity of cyclosprine A.Four weeks later,the rats were sacrificed,blood and kidneys were taken out.Radioimmunoassay was used to study the change of endothelin-1 in plasma,cortex and medulla. Results： Plasma endothelin-1 in CsA-given group has no significant difference with control group. Endothelin- 1 in both cortex and medulla significantly increased in contrast to control group, except medulla in Group D. Conlusion： There is no significant evdence that serum creatine is attached to CsA concentration so chronic nephyrotoxicity of cyclosprine A can＇ t be measured by CsA concentration only. Edothefin-1 is an important cause of renal tubular fibrosis and necrosis in chronic nephrotoxicity of cyclosprine A . In higher dose,Endothelin-1 involves in glomerulus lesion.