ENDOTHELIAL BRD4 PARTICIPATES IN THE DEVELOPMENT OF LUPUS NEPHRITIS
Notice bibliographique
Résumé
O024 / #733 Topic: AS24 - SLE-Treatment Late-Breaking Abstract ABSTRACT CONCURRENT SESSION 04: ADVANCING LUPUS THERAPIES AND INSIGHTS 22-05-2025 1:40 PM - 2:40 PM Background/Purpose Lupus nephritis (LN) is a common and lethal immune-related kidney disease, in which the pathological basis is vasculitis. The core of the LN is the interaction between immune-endothelial cells, but its molecular regulatory mechanism, especially in endothelial, is not clear. BRD4, a member of the BET protein family, is a histone reader that regulates inflammation and proliferation. Previous studies have found that JQ1, a BRD4 inhibitor, can partially relieve the progression of LN in mice, but the mechanism of BRD4 in LN is not clear. Methods We initially utilized the single-cell transcriptome of the kidney from lupus MRL/lpr mice to investigate the predominant cell types and BRD4 expression levels. These findings were subsequently validated in kidney tissues from both lupus patients and mouse models through flow cytometry and immunohistochemistry. Then, female MRL/lpr mice were treated with endothelial specific knockout virus of BRD4 (BRD4 ΔEC -shRNA-AAV) by tail vein injection at the age of 8 weeks. Two model of LN (MRL/lpr and R848 induced mice) were used to test whether new BRD4 inhibitor NWHD870 has a therapeutical effect in vivo. Finally, human glomerular renal endothelial (HRGEC) were transfected with BRD4 overexpression and stimulated with interferon, RNAseq, Co-IP and CHIP-seq were used to explore key transcription factors that interact with BRD4 in endothelial cells. Results First, we identified that renal endothelial cells serve as the primary functional cells in the kidney tissue of lupus mice, and observed a significant upregulation of BRD4 expression in ECs in both lupus patients and mouse models. Then, compared with the virus control group, BRD4 ΔEC -shRNA-AAV injection significantly improved the kidney injury (proteinuria, glomerular basement membrane thickening and IgG deposition, renal mitochondrial abnormalities, tertiary lymphoid structures formation and CD3 + T cell infiltration) of MRL/lpr mice, and ameliorated the lymph node proliferation, serum antibody production, and inflammatory damage of heart and skin. Next, we also treated MRL/lpr mice and R848-induced lupus mice with novel BRD4 inhibitor NHWD870, and found that it had a similar significant therapeutic effect on lupus kidney injury. Furthermore, in HRGEC with BRD4 overexpression, we performed RNAseq and verified that the proinflammatory factors CXCL10, CXCL8 and endothelial damage indicators PECAM1 are significantly increased, and the endothelial cells were performed with a high degree of permeability and inflammatory cell (T cell and Mac) adhesion. Immune-ralated signaling pathway, leukocyte transendothelial transport and glomerulonephritis signaling pathway were enriched. After simulation of IFN, we further found that BRD4 overexpression significantly aggravates IFN-induced endothelial damage, while BRD4 inhibition significantly improves endothelial damage. Finally, in HRGEC, we further find Fli-1 was a key transcription factor binding as well as interaction with BRD4. Overexpression of Fli-1 results in endothelial damage aggravation, while inhibition of Fli-1 improves endothelial damage. BRD4 interacts with Fli-1 in the nucleus and forms a transcription complex evidenced by phase separation in HRGEC. BRD4-Fli-1 transcription complex acts as an enhancer, which regulates the expression of CXCL10, CXCL8 and PECAM1, leading to the progression of LN. Conclusions This study reveals that the high expression of BRD4 in renal endothelial cells is associated with LN, and its molecular mechanism may involve the activation of BRD4-Fli-1 transcription complex, the promotion of the expression of CXCL10, CXCL8 and PECAM1 in renal endothelial cells, and the infiltration of T cells in the kidney. Therefore, BRD4 is a potential therapeutic target for LN.
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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 | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,012 | 0,003 |
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 ».