ENDOTHELIAL BRD4 PARTICIPATES IN THE DEVELOPMENT OF LUPUS NEPHRITIS
Bibliographic record
Abstract
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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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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.012 | 0.003 |
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".