Abstract: FR-PO1052
Apabetalone Reduces Fibrotic Inflammatory and Calcific Factors in Renal Cells and Patient Plasma
Session Information
- CKD Mechanisms: Progression, Fibrosis, and Beyond
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Gilham, Dean, Resverlogix Corp, Calgary, Alberta, Canada
- Wasiak, Sylwia, Resverlogix Corp, Calgary, Alberta, Canada
- Rakai, Brooke D., Resverlogix Corp, Calgary, Alberta, Canada
- Fu, Li, Resverlogix Corp, Calgary, Alberta, Canada
- Tsujikawa, Laura, Resverlogix Corp, Calgary, Alberta, Canada
- Sarsons, Chris, Resverlogix Corp, Calgary, Alberta, Canada
- Carestia, Agostina, Resverlogix Corp, Calgary, Alberta, Canada
- Lebioda, Kenneth E., Resverlogix Corp, Calgary, Alberta, Canada
- Johansson, Jan O., Resverlogix Inc, San Francisco, California, United States
- Sweeney, Michael, Resverlogix Inc, San Francisco, California, United States
- Kalantar-Zadeh, Kamyar, Harbor-UCLA Medical Center, Torrance, California, United States
- Kulikowski, Ewelina, Resverlogix Corp, Calgary, Alberta, Canada
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.
Conclusion
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.