Goodall T, Kind C N, Hammond T G
Fisons plc, Pharmaceutical Division, Loughborough, England.
J Cardiovasc Pharmacol. 1995;26 Suppl 3:S482-5.
Renal damage is a major side effect of the macrolide immunosuppressant FK 506. Although little is known about the underlying mechanism of FK 506 nephrotoxicity, available data suggest that it may be associated with a disturbance in renal hemodynamics, possibly brought about by alterations in the production of vasoactive substances such as endothelin-1 (ET-1). We have investigated the release of ET-1 from primary renal mesangial cells in culture. Mesangial cells derived from rat renal cortex were exposed to a range of FK 506 concentrations (10(-10) to 10(-6) M) or vehicle for up to 6 h. FK 506 caused a significant dose-related increase in ET release. This effect was dependent on cell density and was blocked by co-incubation with FPL 65620, an FK 506 analogue that binds to the FK binding protein (FKBP) and inhibits the immunosuppressive activity of FK 506. These data suggest that mesangial cell ET may play a role in FK 506 nephrotoxicity and that the effect of FK 506 on ET release may be mediated through the FKBP.
肾损伤是大环内酯类免疫抑制剂FK 506的主要副作用。尽管对FK 506肾毒性的潜在机制了解甚少，但现有数据表明，它可能与肾血流动力学紊乱有关，这可能是由血管活性物质如内皮素-1（ET-1）产生的改变所引起的。我们研究了培养的原代肾系膜细胞中ET-1的释放。将来自大鼠肾皮质的系膜细胞暴露于一系列FK 506浓度（10^(-10)至10^(-6) M）或溶剂中长达6小时。FK 506导致ET释放显著剂量相关增加。这种效应取决于细胞密度，并被与FPL 65620共同孵育所阻断，FPL 65620是一种FK 506类似物，可与FK结合蛋白（FKBP）结合并抑制FK 506的免疫抑制活性。这些数据表明系膜细胞ET可能在FK 506肾毒性中起作用，并且FK 506对ET释放的影响可能通过FKBP介导。
