Apabetalone Downregulates Fibrotic, Inflammatory and Calcific Processes in Renal Mesangial Cells and Patients with Renal Impairment
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...
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| Format: | Article |
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MDPI AG
2023-06-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/11/6/1663 |
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| author | Dean Gilham Sylwia Wasiak Brooke D. Rakai Li Fu Laura M. Tsujikawa Christopher D. Sarsons Agostina Carestia Kenneth Lebioda Jan O. Johansson Michael Sweeney Kamyar Kalantar-Zadeh Ewelina Kulikowski |
| author_facet | Dean Gilham Sylwia Wasiak Brooke D. Rakai Li Fu Laura M. Tsujikawa Christopher D. Sarsons Agostina Carestia Kenneth Lebioda Jan O. Johansson Michael Sweeney Kamyar Kalantar-Zadeh Ewelina Kulikowski |
| author_sort | Dean Gilham |
| collection | DOAJ |
| description | 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 <i>IL6</i>, <i>IL1B</i>, and <i>PTGS2</i> 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. |
| first_indexed | 2024-03-11T02:44:39Z |
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| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-11T02:44:39Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-5093b38d0a6348ee86b12a6a465daa752023-11-18T09:26:28ZengMDPI AGBiomedicines2227-90592023-06-01116166310.3390/biomedicines11061663Apabetalone Downregulates Fibrotic, Inflammatory and Calcific Processes in Renal Mesangial Cells and Patients with Renal ImpairmentDean Gilham0Sylwia Wasiak1Brooke D. Rakai2Li Fu3Laura M. Tsujikawa4Christopher D. Sarsons5Agostina Carestia6Kenneth Lebioda7Jan O. Johansson8Michael Sweeney9Kamyar Kalantar-Zadeh10Ewelina Kulikowski11Resverlogix Corp., 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, CanadaResverlogix Corp., 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, CanadaResverlogix Corp., 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, CanadaResverlogix Corp., 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, CanadaResverlogix Corp., 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, CanadaResverlogix Corp., 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, CanadaResverlogix Corp., 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, CanadaResverlogix Corp., 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, CanadaResverlogix Inc., 535 Mission St, 14th Floor, San Francisco, CA 94105, USAResverlogix Inc., 535 Mission St, 14th Floor, San Francisco, CA 94105, USAHarbor-UCLA Medical Center, University of California Los Angeles, 1000 W Carson St, Torrance, CA 90502, USAResverlogix Corp., 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, CanadaEpigenetic 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 <i>IL6</i>, <i>IL1B</i>, and <i>PTGS2</i> 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.https://www.mdpi.com/2227-9059/11/6/1663chronic kidney disease (CKD)fibrosisinflammationgene expressionepigeneticsBET proteins |
| spellingShingle | Dean Gilham Sylwia Wasiak Brooke D. Rakai Li Fu Laura M. Tsujikawa Christopher D. Sarsons Agostina Carestia Kenneth Lebioda Jan O. Johansson Michael Sweeney Kamyar Kalantar-Zadeh Ewelina Kulikowski Apabetalone Downregulates Fibrotic, Inflammatory and Calcific Processes in Renal Mesangial Cells and Patients with Renal Impairment Biomedicines chronic kidney disease (CKD) fibrosis inflammation gene expression epigenetics BET proteins |
| title | Apabetalone Downregulates Fibrotic, Inflammatory and Calcific Processes in Renal Mesangial Cells and Patients with Renal Impairment |
| title_full | Apabetalone Downregulates Fibrotic, Inflammatory and Calcific Processes in Renal Mesangial Cells and Patients with Renal Impairment |
| title_fullStr | Apabetalone Downregulates Fibrotic, Inflammatory and Calcific Processes in Renal Mesangial Cells and Patients with Renal Impairment |
| title_full_unstemmed | Apabetalone Downregulates Fibrotic, Inflammatory and Calcific Processes in Renal Mesangial Cells and Patients with Renal Impairment |
| title_short | Apabetalone Downregulates Fibrotic, Inflammatory and Calcific Processes in Renal Mesangial Cells and Patients with Renal Impairment |
| title_sort | apabetalone downregulates fibrotic inflammatory and calcific processes in renal mesangial cells and patients with renal impairment |
| topic | chronic kidney disease (CKD) fibrosis inflammation gene expression epigenetics BET proteins |
| url | https://www.mdpi.com/2227-9059/11/6/1663 |
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