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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.

SUBMITTER: Renner B

PROVIDER: S-EPMC3810078 | biostudies-other | 2013 Nov

REPOSITORIES: biostudies-other

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Cyclosporine induces endothelial cell release of complement-activating microparticles.

Renner Brandon B Klawitter Jelena J Goldberg Ryan R McCullough James W JW Ferreira Viviana P VP Cooper James E JE Christians Uwe U Thurman Joshua M JM

Journal of the American Society of Nephrology : JASN 20131003 11

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 hypothe ...[more]

PMID: 24092930

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Cyclosporine induces endothelial cell release of complement-activating microparticles.

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Cyclosporine induces endothelial cell release of complement-activating microparticles.

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