Cyclosporine Induces Endothelial Cell Release of Complement-Activating Microparticles

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.

Endothelial Microparticles and Systemic Complement Activation in Patients With Chronic Kidney Disease

“…We previously found that endothelial microparticles can activate the alternative pathway, but we did not identify the molecular cause of this activation 23. To analyze the microparticle proteome, protein was extracted from microparticle pellets and analyzed by the SOMAscan assay (which measures >1100 proteins and can measure the abundance of most proteins in the fmol/L to pmol/L range).…”

“…A number of recent studies have shown that diseases of the vasculature and kidneys, including CKD, are associated with increased numbers of circulating endothelial microparticles 17, 18, 19, 20, 21, 22. We have previously reported that the microparticles released from endothelial cells can, under some conditions, activate the complement system, and that generation of complement‐activating microparticles is associated with vascular and renal injury in mice 23. The complement system is an important part of the body's defense against pathogens, but complement activation also contributes to the pathogenesis of a broad range of diseases, including CVD, ischemia/reperfusion injury, atypical hemolytic uremic syndrome, and renal allograft injury 24, 25, 26, 27, 28, 29.…”

Systematic study of constitutive cyclooxygenase-2 expression: Role of NF-κB and NFAT transcriptional pathways

“…As such, cyclosporin A may provide an important tool to probe the contribution of renal COX-2 to the cardiovascular side effects attributed to NSAIDs use. In this regard, it is interesting to note that in animal models (30) and in humans (31), cyclosporin A, as with COX-2 inhibitors, increases circulating levels of the naturally occurring eNOS inhibitor ADMA; a mechanism that we recently highlighted as relevant to the cardiovascular side effects associated with NSAIDs (5). Second and perhaps more importantly, our observations lay groundwork for the idea that targeting COX-2 at the transcriptional level could dissociate antiinflammatory benefit of NSAIDs from their cardio-renal side effects.…”

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“…5,7,10,12 A recent experimental study showed that cyclosporine induces increased endothelial release of complement-activating microparticles, suggesting that blocking complement activation may help to alleviate the condition. 20 Carmona and associates found that cyclosporine alone and the combination of tacrolimus and sirolimus had an increased proinflammatory effect on endothelial cells; however, only cyclosporine showed additional prothrombotic effects. 21 The incidence of de novo TMA was recently shown to be 3% in renal allografts without evidence of AHR; however, all of the study patients were receiving tacrolimus and none were using Abbreviations: ACR, acute cellular rejection; TMA, thrombotic microangiopathy mammalian target of rapamycin inhibitors.…”