Apabetalone Downregulates Fibrotic, Inflammatory and Calcific Processes in Renal Mesangial Cells and Patients with Renal Impairment

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.

Apabetalone (RVX-208): A Potential Epigenetic Therapy for the Treatment of Cardiovascular, Renal, Neurological, Viral, and Cancer Disorders

“…52 Consistent with this, in human renal mesangial cells, apabetalone also reduced the gene expression and the protein level of ALP induced by TGFβ. 47 Taken together, these results clearly indicate that apabetalone has a direct effect on the expression of ALP.…”

“…In parallel to the clinical data, another experiment using apabetalone in human renal mesangial cells exposed to tissue growth factor-β (TGFβ) demonstrated that apabetalone prevents upregulation of α-smooth muscle actin, reduces collagen production, and downregulates key inflammatory and fibrotic markers such as IL-6, IL-1β, cyclooxygenase-2, fibronectin, and periostin. 47 Overall, these findings provide more evidence that apabetalone may help in treating renal dysfunction (Table 1).…”

“…Conversely, a BET inhibitor like apabetalone reduces extracellular calcium deposition and matrix mineralization markers in vascular smooth muscle cells probably by downregulating the mRNA, protein, and enzyme levels of alkaline phosphatase (ALP) . Consistent with this, in human renal mesangial cells, apabetalone also reduced the gene expression and the protein level of ALP induced by TGFβ . Taken together, these results clearly indicate that apabetalone has a direct effect on the expression of ALP.…”

“…These proteins are critical players in renal impairment including inflammation, vascular calcification, cell adhesion, thrombosis, extracellular matrix remodeling, oxidative stress, and metabolism . Interestingly, apabetalone was able to reduce the expression of inflammation markers such as IL-6, downregulate fibrotic markers such as fibronectin, and counteract the activation of most renal disease pathways, clearly indicating a potential of apabetalone for the treatment of chronic kidney disease , (Table ). In parallel to the clinical data, another experiment using apabetalone in human renal mesangial cells exposed to tissue growth factor-β (TGFβ) demonstrated that apabetalone prevents upregulation of α-smooth muscle actin, reduces collagen production, and downregulates key inflammatory and fibrotic markers such as IL-6, IL-1β, cyclooxygenase-2, fibronectin, and periostin .…”

The Role of Selected Epigenetic Pathways in Cardiovascular Diseases as a Potential Therapeutic Target

“…In pooled phase 2 data analyses, APA reduced the rate of cardiovascular events by approximately 60%. However, in the BETOnMACE Phase III study, APA reduced the risk of major adverse cardiac events (MACE) by 50% in the chronic kidney disease subpopulation, indicating a beneficial effect along the kidney–heart axis [ 94 , 95 ]. Certainly, further clinical trials are needed to better investigate the safety and efficacy of APA in the treatment of CVDs.…”