Related Experiment Video
Updated: Jul 25, 2025
Mechanism of Kemeng Fang's Inhibition of Podocyte Apoptosis in Rats with Membranous Nephropathy through the PI3K/AKT Signaling Pathway
Published on: August 23, 2024
Apabetalone Downregulates Fibrotic, Inflammatory and Calcific Processes in Renal Mesangial Cells and Patients with
Dean Gilham1, Sylwia Wasiak1, Brooke D Rakai1
1Resverlogix Corp., 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, Canada.
Abstract:
Epigenetic mechanisms are implicated in transcriptional programs driving chronic kidney disease (CKD). Apabetalone is an orally available inhibitor of bromodomain and extraterminal (BET) proteins, which are epigenetic readers that modulate gene expression. In the phase 3 BETonMACE trial, apabetalone reduced risk of major adverse cardiac events (MACE) by 50% in the CKD subpopulation, indicating favorable effects along the kidney-heart axis. Activation of human renal mesangial cells (HRMCs) to a contractile phenotype that overproduces extracellular matrix (ECM) and inflammatory cytokines, and promotes calcification, frequently accompanies CKD to drive pathology. Here, we show apabetalone downregulated HRMC activation with TGF-β1 stimulation by suppressing TGF-β1-induced α-smooth muscle actin (α-SMA) expression, α-SMA assembly into stress fibers, enhanced contraction, collagen overproduction, and expression of key drivers of fibrosis, inflammation, or calcification including thrombospondin, fibronectin, periostin, SPARC, interleukin 6, and alkaline phosphatase. Lipopolysaccharide-stimulated expression of inflammatory genes IL6, IL1B, and PTGS2 was also suppressed. Transcriptomics confirmed apabetalone affected gene sets of ECM remodeling and integrins. Clinical translation of in vitro results was indicated in CKD patients where a single dose of apabetalone reduced plasma levels of key pro-fibrotic and inflammatory markers, and indicated inhibition of TGF-β1 signaling. While plasma proteins cannot be traced to the kidney alone, anti-fibrotic and anti-inflammatory effects of apabetalone identified in this study are consistent with the observed decrease in cardiovascular risk in CKD patients.
Insights
Apabetalone, a bromodomain and extraterminal (BET) protein inhibitor, reduces chronic kidney disease (CKD) cell activation and inflammation. This epigenetic therapy shows promise for improving kidney health and reducing cardiovascular risk in CKD patients.
Area of Science:
- Nephrology
- Epigenetics
- Cardiovascular Medicine
Background:
- Epigenetic mechanisms drive transcriptional changes in chronic kidney disease (CKD).
- Bromodomain and extraterminal (BET) proteins are epigenetic readers influencing gene expression.
- Apabetalone is an oral BET inhibitor with demonstrated cardiovascular benefits in CKD patients.
Purpose of the Study:
- To investigate apabetalone's effects on activated human renal mesangial cells (HRMCs) in vitro.
- To explore apabetalone's impact on fibrotic, inflammatory, and calcification pathways in CKD.
- To assess the clinical translation of apabetalone's effects in CKD patients.
Main Methods:
- HRMCs were stimulated with TGF-β1 and lipopolysaccharide to mimic CKD activation.
- Apabetalone's effects on α-smooth muscle actin (α-SMA), extracellular matrix (ECM) production, and inflammatory gene expression were measured.
- Transcriptomic analysis was performed to identify affected gene sets.
- Plasma levels of pro-fibrotic and inflammatory markers were assessed in CKD patients after apabetalone administration.
Main Results:
- Apabetalone suppressed TGF-β1-induced HRMC activation, including α-SMA expression, ECM overproduction, and fibrosis-related gene expression.
- Apabetalone inhibited lipopolysaccharide-stimulated inflammatory gene expression (IL6, IL1B, PTGS2).
- Transcriptomics revealed apabetalone's impact on ECM remodeling and integrin gene sets.
- In CKD patients, a single apabetalone dose reduced plasma pro-fibrotic and inflammatory markers, suggesting TGF-β1 signaling inhibition.
Conclusions:
- Apabetalone downregulates key pathways driving kidney fibrosis, inflammation, and calcification in vitro.
- The findings suggest apabetalone's anti-fibrotic and anti-inflammatory actions contribute to its observed cardiovascular benefits in CKD.
- Apabetalone demonstrates potential as a therapeutic agent for managing CKD progression and associated cardiovascular risks.
Related Concept Videos
01:26Heart Failure Drugs: Inhibitors of Renin-Angiotensin System
01:25Antihypertensive Drugs: Direct Renin Inhibitors
01:30Antihypertensive Drugs: Angiotensin-Converting Enzyme Inhibitors
01:17Factors Affecting Renal Clearance: Renal Impairment
One condition associated with renal failure is uremia. Uremia is characterized by impaired glomerular filtration and fluid accumulation in the body. This condition hinders the renal clearance of drugs, resulting in drug accumulation and potential...
01:28Chronic Kidney Disease III: Interprofessional Care
01:24Chronic Kidney Disease II: Clinical Manifestations