Su Q, Weber L, Le Hir M, Zenke G, Ryffel B
Institute of Toxicology, University of Zürich, Schwerzenbach.
Ren Physiol Biochem. 1995 May-Jun;18(3):128-39. doi: 10.1159/000173910.
Cyclosporin A (CsA; 50 mg/kg) and Fujimycine (FK506; 5 mg/kg), but not the related macrolide immunosuppressant rapamycin (5 mg/kg), caused a reduction of glomerular filtration rate, degenerative changes of proximal tubular epithelium, and hypertrophy of the juxtaglomerular apparatus in male Wistar rats when given for 10 days. The molecular mechanisms of CsA and FK506 toxicity were investigated. Cyclophilin A and FK506-binding protein, the main intracytoplasmic receptors for CsA and FK506, respectively, were each detected in renal tissue extract. In the kidney, high levels of immunoreactive and enzymatically active calcineurin were found which were inhibited by the immunosuppressants CsA and FK506, but not by rapamycin. Finally, specific immunophilin-drug-calcineurin complexes formed only in the presence of CsA and FK506, but not rapamycin. These results suggest that the nephrotoxic effects of CsA and FK506 is likely mediated through binding to renal immunophilin and inhibiting calcineurin phosphatase.
环抱霉素A（CsA；50毫克/千克）和藤霉素（FK506；5毫克/千克），但不包括相关的大环内酯类免疫抑制剂雷帕霉素（5毫克/千克），在雄性Wistar大鼠中连续给药10天时，会导致肾小球滤过率降低、近端肾小管上皮细胞发生退行性变化以及肾小球旁器肥大。对CsA和FK506毒性的分子机制进行了研究。分别在肾组织提取物中检测到了亲环蛋白A和FK506结合蛋白，它们分别是CsA和FK506主要的胞浆内受体。在肾脏中发现了高水平的免疫反应性和酶活性钙调神经磷酸酶，它们受到免疫抑制剂CsA和FK506的抑制，但不受雷帕霉素的抑制。最后，特异性亲免素-药物-钙调神经磷酸酶复合物仅在存在CsA和FK506时形成，而雷帕霉素不存在时则不形成。这些结果表明，CsA和FK506的肾毒性作用可能是通过与肾亲免素结合并抑制钙调神经磷酸酶介导的。
