The Lectin-Like Domain of Thrombomodulin Protects Against Diabetic Nephropathy by Inhibiting Complement Activation
Bibliographic record
Abstract
Abstract Abstract 654 Introduction: Thrombomodulin (TM) is type 1 transmembrane glycoprotein predominately expressed on vascular endothelial cells. TM consists of distinct structural domains, which enable interaction with multiple ligands and thus modulation of coagulation, fibrinolysis, complement activation, inflammation, cell proliferation, and apoptosis. We have previously shown that TM protects against diabetic nephropathy (dNP) through activation of protein C (PC), which inhibits glomerular apoptosis. Recent studies showed that TM mediates cytoprotective effects independent of PC activation through it's lectin-like domain (LLD). The LLD directly interferes with complement activation and protect against arthritis. dNP is associated with an infiltration of inflammatory cells, enhanced cytokine production, and complement activation raising the question whether endothelial TM may protect against DN through a dual mechanism depending on (a) PC activation and (b) complement inhibition through the LLD. Methods: Experimental dNP was evaluated in mice with targeted deletion of the LLD of TM (TMLed/Led mice). Persistent hyperglycemia was induced using streptozotocin in TMLed/Led mice and in control wild type mice (wt). Subgroups of mice were treated with low molecular heparin (LMWH) to inhibit complement activation and coagulation activation, fondaparinux to inhibit coagulation activation, or treated with minocycline to inhibit glomerular apoptosis. After 28 weeks albuminuria was determined and mice were sacrificed to isolated tissues and blood samples for analyses. Results: Albuminuria, histological indices of diabetic nephropathy and glomerular C3 deposition were increased in diabetic wt mice and further increased in diabetic TMLed/Led mice. Only treatment with LMWH, but not with fondaparinux corrected the aggravated DN in TMLed/Led mice, despite equal anticoagulation in both groups. Glomerular complement depositions (immunohistochemistry) were significantly reduced following in vivo LMWH treatment, but no in fondaparinux treated mice. In vitro, endothelial cells expressing a TM mutant lacking the LLD had diminished capacity to bind and inactivate C3b and were thus sensitive to complement mediated cell lyses. Of note, apoptosis (TUNEL) and expression levels of apoptosis regulators (p53, Bax/Blc-2 ratio, Western) did not differ between untreated or LMWH/fondaparinux treated diabetic TMLed/Led mice, indicating that the protective effect of the LLD is independent of apoptosis inhibition. Consistently, inhibition of apoptosis with minocycline failed to normalize albuminuria or prevent histological indices of dNP in diabetic TMLed/Led mice. Likewise, we did not observe difference in HMGB-1 levels within the kidney or in plasma sample, and inhibition of HMGB-1 using sodium Tanshinon II asilate failed to reduce dNP in diabetic TMLed/Led mice. Discussion and Conclusion: We identify a novel pathway through which endothelial TM protects against dNP. TM protects against dNP by inhibiting complement activation through its LLD. This function is independent of the recently identified activated PC dependent inhibition of glomerular apoptosis. Thus, endothelial TM prevents dNP through two independent pathways. These results provide further experimental support for a causative role of endothelial dysfunction for DN. Disclosures: No relevant conflicts of interest to declare.
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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 | 0.001 |
| 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".