Cyclosporine-Induced Endothelial Injury and Complement Activation Is Caused by Impaired Complement Factor H Binding to the Glycocalyx
Bibliographic record
Abstract
Background: Calcineurin inhibitors are associated with nephrotoxicity, endothelial cell (EC) dysfunction and thrombotic microangiopathy. Evolving evidence suggests a central role for complement dysregulation in the pathogenesis of CNI-induced thrombotic microangiopathy. However, the exact mechanism of calcineurin-induced complement-mediated injury remains unknown. Methods: In an in-vitro model utilising Blood Outgrowth EC (BOEC) from healthy donors, we evaluated the effects of cyclosporine (CsA) on EC injury, complement activation (C3c, C9) and regulation (CD46, CD55, CD59 and complement factor H [CFH]) on EC surfaces, and on the EC glycocalyx, utilising flow cytometry, Western blot, and immunofluorescence imaging. Functional activity of CFH was assessed via CFH co-factor assay. Co-immunoprecipitation of Angiopoietin-2 (Angpt-2), Angiopoietin-1 (Angpt-1) and Tie2 was assessed by Western blot. Results: CsA resulted in a dose and time dependent enhancement of EC complement deposition and EC death. CsA (10 μg/ml for 24 h) led to upregulation of CD46, CD55 and CD59 on EC surface. CsA led to Angpt-2 mediated breakdown of the EC glycocalyx, which was mitigated by Angpt-1. This EC glycocalyx breakdown led to decrease in CFH surface binding and surface cofactor activity. Conclusions: Our findings confirm a role for complement in CsA-induced EC injury, and suggest Angpt-2 mediated glycocalyx abolishment, induced by CsA, as a mechanism leading to complement alternative pathway dysregulation via decreased CFH surface binding. Insights into this mechanism may provide a potential therapeutic target that might lead to improved patient outcomes which is subject to further studies. It might also apply to other thrombotic microangiopathies, in which a role for complement has so far not been recognized.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".