Ghiggeri G M, Altieri P, Oleggini R, Spada F, Ginevri F, Perfumo F, Gusmano R
Divisione di Nefrologia, Istituto G. Gaslini, Genoa, Italy.
Eur J Pharmacol. 1994 Apr 4;270(2-3):195-201. doi: 10.1016/0926-6917(94)90063-9.
Extracellular matrix deposition in mesangial areas leading to glomerulosclerosis is the major side effect of protracted therapies with cyclosporin A. In order to define any direct correlation between a chronic therapy with the drug and glomerulosclerosis we studied the effects of cyclosporin A on extracellular matrix production by human mesangial cells in culture. By immunoprecipitation and sodium dodecyl sulfate polyacrylamide electrophoresis (SDS-PAGE) of [3H]proline-labeled mesangial cells it was found that cyclosporin A induced a dose-dependent increase in total collagen synthesis (+80%), corresponding to a net increment in collagen III (+120%) and in a component with 70 kDa molecular weight which was produced only in negligible amount by mesangial cells under standard conditions. This collagen was characterized by cyanogen bromide digestion and finger print analysis as a novel molecule, not sharing any peptide composition similarities with the already characterized collagens. These data indicate that cyclosporin A stimulates the synthesis by mesangial cells of selected collagens, mainly collagen III and a new low molecular weight component. This mechanism may be relevant in cyclosporin A induced glomerulosclerosis occurring during protracted therapies with the drug.
环孢素A长期治疗导致肾小球系膜区细胞外基质沉积进而引发肾小球硬化，这是其主要副作用。为明确该药物的长期治疗与肾小球硬化之间是否存在直接关联，我们研究了环孢素A对培养的人肾小球系膜细胞产生细胞外基质的影响。通过对[3H]脯氨酸标记的系膜细胞进行免疫沉淀和十二烷基硫酸钠聚丙烯酰胺凝胶电泳（SDS-PAGE），发现环孢素A可诱导总胶原蛋白合成呈剂量依赖性增加（增加80%），这对应于III型胶原蛋白净增加（增加120%）以及一种分子量为70 kDa的成分增加，该成分在标准条件下系膜细胞仅产生极少量。经溴化氰消化和指纹分析鉴定，这种胶原蛋白是一种新分子，与已鉴定的胶原蛋白在肽组成上没有任何相似之处。这些数据表明，环孢素A刺激系膜细胞合成特定的胶原蛋白，主要是III型胶原蛋白和一种新的低分子量成分。这一机制可能与环孢素A长期治疗期间引发的肾小球硬化有关。
