Apabetalone Reduces Fibrotic Inflammatory and Calcific Factors in Renal Cells and Patient Plasma
Bibliographic record
Abstract
Background: The BET protein inhibitor apabetalone downregulates the expression of genes involved in fibrosis, inflammation and calcification, processes that drive cardiovascular disease and kidney dysfunction. In the phase 3 BETonMACE trial, apabetalone reduced the risk of major acute cardiac event (MACE) by 50% in the subpopulation with CKD (eGFR<60) implying favorable effects on the kidney-heart axis. Here we examine effects of apabetalone on processes of nephropathy in human renal mesangial cells (MCs) and assess plasma proteomics in CKD subjects or controls. Methods: MCs were stimulated with TGF-β1, a pro-fibrotic cytokine, ± 1 to 25μM apabetalone. Gene expression was measured by real-time PCR, protein secretion by ELISA, smooth muscle actin (α-SMA) by immunofluorescence, collagen with picrosirius red, cell contraction in collagen gels and tissue non-specific alkaline phosphatase (TNAP) activity in biochemical assays. Plasma proteomics (Somascan 1.3) were evaluated in 8 CKD subjects (eGFR <30) and 8 controls after a 100mg dose of apabetalone. Ingenuity Pathway Analysis (IPA) analyzed upstream regulators. Results: In MCs, apabetalone downregulated TGF-β1 stimulated α-SMA gene expression up to 89% and abolished α-SMA stress fiber formation and cell contraction. Collagen deposition was reduced to unstimulated levels. mRNA and enzyme activity levels for TNAP, involved in calcification, were reduced up to 96%. Apabetalone countered TGF-β1 induced gene expression and protein secretion of key drivers of fibrosis and inflammation including thrombospondin, fibronectin, periostin, osteonectin and IL-6 (p<0.001 for all MC results). Plasma levels of these factors were reduced 12h after taking apabetalone specifically in CKD subjects. IPA predicted TGF-β1 pathway activation in CKD vs controls, and its inhibition after the dose of apabetalone. Conclusions: Through epigenetic regulation of transcription in MCs, apabetalone suppresses fibrotic, inflammatory and calcific factors associated with CKD. Plasma levels of fibrotic and inflammatory proteins were reduced specifically in CKD subjects. This may, in part, explain reduced MACE risk in the CKD subpopulation receiving apabetalone in BETonMACE, which will be further evaluated in future phase 3 trials. Funding: Commercial Support - Resverlogix Corp.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".