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Cyclosporine Induces Endothelial Cell Release of Complement-Activating Microparticles

发布于：2013年10月14日    文字：【大】【中】【小】

J Am Soc Nephrol. 2013 Oct 3. [Epub ahead of print]

Cyclosporine Induces Endothelial Cell Release of Complement-Activating Microparticles.

Renner B, Klawitter J, Goldberg R, McCullough JW, Ferreira VP, Cooper JE, Christians U, Thurman JM.

Source

Department of Medicine and.

Abstract

Defective control of the alternative pathway of complement is an important risk factor for several renal diseases, including atypical hemolytic uremic syndrome. Infections, drugs, pregnancy, and hemodynamic insults can trigger episodes of atypical hemolytic uremic syndrome in susceptible patients. Although the mechanisms linking these clinical events with disease flares are unknown, recent work has revealed that each of these clinical conditions causes cells to release microparticles. We hypothesized that microparticles released from injured endothelial cells promote intrarenal complement activation. Calcineurin inhibitors cause vascular and renal injury and can trigger hemolytic uremic syndrome. Here, we show that endothelial cells exposed to cyclosporine in vitro and in vivo release microparticles that activate the alternative pathway of complement. Cyclosporine-induced microparticles caused injury to bystander endothelial cells and are associated with complement-mediated injury of the kidneys and vasculature in cyclosporine-treated mice. Cyclosporine-induced microparticles did not bind factor H, an alternative pathway regulatory protein present in plasma, explaining their complement-activating phenotype. Finally, we found that in renal transplant patients, the number of endothelial microparticles in plasma increases 2 weeks after starting tacrolimus, and treatment with tacrolimus associated with increased C3 deposition on endothelial microparticles in the plasma of some patients. These results suggest that injury-associated release of endothelial microparticles is an important mechanism by which systemic insults trigger intravascular complement activation and complement-dependent renal diseases.

补体旁路调节缺陷是多种肾脏疾病发生的重要危险因素，包括不典型溶血尿毒综合征(aHUS)。感染、药物、妊娠及血液动力学失调可导致aHUS在易感人群中发作。尽管这些临床事件导致疾病发生的机制还不清楚，最近的一些研究提示这些临床情况可以导致细胞释放微颗粒。本研究中我们假设受损的内皮细胞释放的微颗粒可以导致肾脏局部补体的激活。钙调磷酸酶抑制剂造成的血管及肾脏损伤可以导致HUS的发生。本研究中我们证实了在体内或体外用环孢霉素刺激的内皮细胞可以释放微颗粒，进而激活补体旁路途径。环孢霉素刺激的微颗粒释放导致了作为旁观者的内皮细胞的损伤，这与环孢霉素处理的小鼠体内补体介导的肾脏及血管损伤相关。环孢霉素刺激后内皮释放的微颗粒不与H因子(循环中的旁路抑制因子)结合，解释了微颗粒可以激活补体的原因。最终，我们发现在肾移植的患者体内内皮细胞释放的微颗粒含量在开始用他克莫司治疗2周时开始上升，且在一些患者体内，他克莫司治疗与循环中内皮细胞微颗粒上沉积的C3含量增加相关。这些结果提示损伤相关的内皮细胞微颗粒的释放是血管内补体激活和补体介导的肾脏疾病发生的重要机制。