药物中断对慢性环孢素A肾毒性可逆性的机制研究

Mechanism of the reversibility of chronic cyclosporine nephrotoxicity after drug withdrawal

目的 探讨长期停用环孢素A(CsA)对已建立的慢性CsA肾毒性可逆性的机制。方法 SD大白鼠给予皮下注射CsA(15mg·kg^(-1)·d^(-1))5周,建立慢性CsA肾毒性模型,然后停药观察5周及10周。检测各组大鼠的体重、收缩压及肾功能。肾组织病理改变以PAS、三色染色观察。免疫组织化学染色检测肾间质炎性细胞浸润。Northern印迹检测骨调素(OPN)和转化生长因子(TGF-β1)mRNA的表达。结果 与对照组相比,慢性CsA肾毒性组体重减轻、肾功能下降、肾入球动脉病变、间质大量ED-1阳性细胞的浸润及带状纤维化,OPN和TGF-β1 mRNA的表达明显上调。停用CsA后上述各项指标均逆转。OPN和TGF-β1 mRNA的表达下调呈时间依赖性,并与间质带状纤维化程度正相关。结论 长期停用CsA可使慢性CsA肾毒性逆转,其机制与OPN和TGF-β1基因的表达下调有一定关系。

Objective To explore the mechanism of the reversibility of chronic cyclosporine (CsA) nephrotoxicity in rats after long-term drug withdrawal. Methods Chronic CsA nephrotoxicity was induced in Sprague-Dawley rats by administering CsA(15 mg . kg-1. d-1) for 5 weeks,and then the effect of drug withdraw for 5 and 10 weeks was observed. Body weight,systolic blood pressure,and renal function were monitored. In addition,renal histopathology(arteriolopathy,ED-1-positive cells,and tubulointerstitial fibrosis) and expression of osteopontin(OPN) and transforming growth factor(TGF) -β1 mRNA was examined. Results Compared with the control rats,CsA-treated rats showed loss of body weight,deterioration in renal function and development of typical histopathology. All of these above parameters were significantly reversed,meanwhile,the upregulation of OPN and TGF-β1 mRNA expression decreased significantly at 5th and 10th week after CsA withdrawal. Of note,the decreased OPN and TGF-β1 mRNA expression was positively correlated with the reduction in the tubulointerstitial fibrosis score. Conclusion The established chronic CsA nephrotoxicity is reversible after long-term CsA discontinuation,and the mechanism may be associated with the down-regulation of OPN and TGF-β1 mRNA expression.