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Abstract: PO2434

Apabetalone Downregulates Fibrotic, Inflammatory and Calcific Processes in Renal Mesangial Cells: Mechanism for Reduced Cardiac Events in CKD Patients

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Gilham, Dean, Resverlogix Corp, Calgary, Alberta, Canada
  • Fu, Li, Resverlogix Corp, Calgary, Alberta, Canada
  • Rakai, Brooke D., Resverlogix Corp, Calgary, Alberta, Canada
  • Wasiak, Sylwia, Resverlogix Corp, Calgary, Alberta, Canada
  • Tsujikawa, Laura, Resverlogix Corp, Calgary, Alberta, Canada
  • Sarsons, Chris, Resverlogix Corp, Calgary, Alberta, Canada
  • Stotz, Stephanie, Resverlogix Corp, Calgary, Alberta, Canada
  • Johansson, Jan O., Resverlogix Inc., San Francisco, California, United States
  • Sweeney, Michael, Resverlogix Inc., San Francisco, California, United States
  • Wong, Norman Cw, Resverlogix Corp, Calgary, Alberta, Canada
  • Kalantar-Zadeh, Kamyar, University of California Irvine, Irvine, California, United States
  • Kulikowski, Ewelina, Resverlogix Corp, Calgary, Alberta, Canada
Background

Major adverse cardiac events (MACE) are prevalent in patients with chronic kidney disease (CKD). Apabetalone inhibits BET proteins, which regulate expression of genes involved in fibrosis, inflammation & calcification. In the phase 3 BETonMACE trial, apabetalone reduced MACE in patients with CKD (eGFR<60) implying favorable effects on the kidney-heart axis. Here we examine apabetalone’s impact on pathways of nephropathy in human renal mesangial cells (HRMCs).

Methods

HRMCs were stimulated with TGF-β1 or LPS ± 1-25µM apabetalone. Gene expression was measured by real-time PCR & RNA-seq. Smooth muscle actin (a-SMA) was examined by immunofluorescence & alkaline phosphatase (TNALP) activity in biochemical assays. RNA-seq from TGF-β1 stimulated HRMC was evaluated by GO and Ingenuity Pathway Analysis (IPA).

Results

In HRMCs, apabetalone suppressed TGF-b1 induced pro-fibrotic gene expression including (a) a-SMA, a fibrotic marker, by 90% p<0.001 & de novo a-SMA protein production (b) fibronectin, an extracellular matrix (ECM) component, by 44% p<0.001 (c) NOX4, promoting reactive oxygen species (ROS) production, by 82% p<0.001 (d) TNALP, promoting calcification, by 96% & TNALP activity by 96% p<0.001. Apabetalone opposed LPS induced inflammatory gene expression: IL6 by 94%, IL1B by 95% & PTGS2 (COX2) by 94% p<0.001.

In GO, ECM gene sets were in the top 20 affected by apabetalone, indicating reduced fibrosis. IPA predicted inhibition of NfkB-RelA and NFkB complex to suppress inflammation, and activation of glucose utilization & tolerance of ROS production pathways, such as Oxidative Phosphorylation (z-score 5.7 p<0.01 at 25µM; z-score 3.5 p>0.05 at 5µM) and NRF2-Mediated Oxidative Stress Response (z score 2.3 p<0.001 at 25µM; z-score 1.6 p<0.001 at 5µM).

Conclusion

Apabetalone downregulates responses to TGF-β1 or LPS that promote fibrosis, inflammation & calcification in HRMCs. Changes in energy metabolism pathways predict apabetalone enables HRMC to cope with elevated glucose. Our results provide mechanistic insight into reduced MACE in CKD patients receiving apabetalone in the BETonMACE trial, & predict efficacy in the upcoming phase 3 BETonMACE2 trial.

Funding

  • Commercial Support – Resverlogix Corp.