The Lectin-Like Domain of Thrombomodulin Protects Against Diabetic Nephropathy by Inhibiting Complement Activation
Notice bibliographique
Résumé
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.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».