一种新型环孢素A慢性肾毒性大鼠模型的建立

目的 建立新型环孢素A慢性肾毒性大鼠模型并探讨其特点.方法 雄性SD大鼠(正常盐饮食)分为假手术组(sham-ADX组)、肾上腺切除组(ADX组)及肾上腺切除及注射环孢素A组(CsA组).后两组先行双侧肾上腺切除术,2周后分别注射安慰剂或环孢素A.6周后检测尿蛋白定量、肌酐清除率、血和尿醛固酮及钠钾水平、肾组织醛固酮及其合成酶CYP11B2表达和肾组织病理改变.结果 ADX和CsA组术后2d血和尿未检测到醛固酮,尿钠增多、血钠减低,尿钾减少、血钾升高.6周实验结束时,CsA组大鼠尿蛋白增加、肌酐清除率下降,肾组织病理检查呈现明显肾间质纤维化;ADX和CsA组大鼠肾组织CYP11B2 mRNA表达和醛固酮均显著上调,再次出现血和尿醛固酮,钠钾代谢紊乱改善.结论 用肾上腺切除和正常盐饮食制作环孢素A慢性肾毒性大鼠模型成功.消除循环醛固酮后,肾组织醛固酮表达上调并释放入血,维持钠钾平衡.

Establishment of A New Rat Model of Chronic Cyclosporine A Nephrotoxicity

Objective To establish a new rat model of chronic cyclosporine A nephrotoxicity and ex-plore its features. Methods Totally 24 male SD rats were equally randomized divided into 3 groups: sham-adrenalectomized (sham-ADX) group, ADX group and ADX plus cyclosporine A (CsA) group. Rats in ADX and CsA group first underwent adrenalectomy, followed by the administration of placebo or dexamethasone, re-spectively. Rats in sham-ADX group received sham adrenalectomy and destilled water as control. Six weeks lat-er, all rats were sacrificed and the following indicators were evaluated; urine protein excretion, creatinine clearance, aldosterone level in serum and urine, aldosterone level and its synthase CYP11B2 gene expression in kidney, serum natrium and potassium, urine natrium and potassium excretion, and tubulointerstitial fibrosis by masson trichrome stain. Results In ADX and CsA group, serum and urine aldosterone were undetectable on the second post-operative day, with other observations including natriuresis, hyponatremia, decreased urine potassium excretion, and hyperpotassaemia, suggesting that adrenals were removed intactly and the adrenalecto- my was successful Rats in CsA group showed increased urine protein, decreased creatinine clearance and tu-bulointerstitial fibrosis, suggesting that a model of chronic CsA nephrotoxity was successfully established. At the endpoint, serum potassium, serum aldosterone, urine potassium and urine aldosterone excretion partially re-trieved. Natrium in serum and urine was not significant different between ADX group/CsA group and sham-ADX group. Local renal aldosterone and its gene expression were remarkably upregulated. Conclusions We suc-cessfully established a new rat model of chronic CsA nephrotoxicity by adrenalectomy without low sodium diet After adrenalectomy, local renal aldosterone in kidney may compensate for circulatory aldosterone deficit to maintain electrolyte balance.