Apabetalone Downregulates Fibrotic, Inflammatory and Calcific Processes in Renal Mesangial Cells and Patients with Renal Impairment.
BET proteins
apabetalone
chronic kidney disease (CKD)
epigenetics
fibrosis
gene expression
inflammation
Journal
Biomedicines
ISSN: 2227-9059
Titre abrégé: Biomedicines
Pays: Switzerland
ID NLM: 101691304
Informations de publication
Date de publication:
08 Jun 2023
08 Jun 2023
Historique:
received:
16
05
2023
revised:
04
06
2023
accepted:
06
06
2023
medline:
28
6
2023
pubmed:
28
6
2023
entrez:
28
6
2023
Statut:
epublish
Résumé
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
Identifiants
pubmed: 37371758
pii: biomedicines11061663
doi: 10.3390/biomedicines11061663
pmc: PMC10295623
pii:
doi:
Types de publication
Journal Article
Langues
eng
Références
Am J Respir Crit Care Med. 2019 Oct 1;200(7):910-920
pubmed: 31042405
Atherosclerosis. 2019 Jan;280:75-84
pubmed: 30476723
J Am Soc Nephrol. 2017 Mar;28(3):953-962
pubmed: 27647855
J Am Soc Nephrol. 1993 Jul;4(1):58-61
pubmed: 8400070
Cent Eur J Immunol. 2021;46(4):494-501
pubmed: 35125949
Acta Pharmacol Sin. 2018 Feb;39(2):222-229
pubmed: 28858296
Front Immunol. 2017 Apr 21;8:405
pubmed: 28484449
Antioxidants (Basel). 2018 Aug 08;7(8):
pubmed: 30096767
Int J Mol Sci. 2019 Dec 30;21(1):
pubmed: 31906008
Nephrol Dial Transplant. 2008 Dec;23(12):3880-7
pubmed: 18676351
J Biol Chem. 1999 Nov 5;274(45):32145-52
pubmed: 10542250
Biomedicines. 2021 Apr 18;9(4):
pubmed: 33919584
Exp Mol Pathol. 1992 Apr;56(2):132-43
pubmed: 1587339
Front Mol Biosci. 2021 Sep 03;8:728777
pubmed: 34540900
Compr Physiol. 2013 Apr;3(2):957-76
pubmed: 23720336
J Am Soc Nephrol. 2002 Oct;13(10):2600-10
pubmed: 12239251
Nat Rev Nephrol. 2017 Jul;13(7):429-442
pubmed: 28502983
Biochem J. 1965 Oct;97(1):95-103
pubmed: 16749130
Adv Drug Deliv Rev. 2010 Nov 30;62(14):1337-43
pubmed: 20828589
Eur J Pharmacol. 2011 Mar 1;654(1):117-21
pubmed: 21147091
EBioMedicine. 2021 May;67:103370
pubmed: 33971401
Kidney Int. 2012 Jun;81(12):1226-38
pubmed: 22418977
Atherosclerosis. 2014 Sep;236(1):91-100
pubmed: 25016363
Diabetologia. 2005 Dec;48(12):2650-60
pubmed: 16270194
Kidney Blood Press Res. 2018;43(2):449-457
pubmed: 29566379
Matrix Biol. 2018 Aug;68-69:28-43
pubmed: 29288716
OMICS. 2012 May;16(5):284-7
pubmed: 22455463
J Cardiol. 2016 May;67(5):412-7
pubmed: 26363819
Nat Rev Nephrol. 2011 Oct 18;7(12):684-96
pubmed: 22009250
Adv Exp Med Biol. 2019;1165:165-194
pubmed: 31399966
Exp Cell Res. 2019 Oct 15;383(2):111507
pubmed: 31356816
J Am Soc Nephrol. 2014 Aug;25(8):1724-36
pubmed: 24578131
Am J Physiol Renal Physiol. 2003 Feb;284(2):F243-52
pubmed: 12529270
Clin Epigenetics. 2019 Jul 12;11(1):102
pubmed: 31300040
Front Pharmacol. 2019 Nov 08;10:1315
pubmed: 31780938
J Clin Invest. 2003 Nov;112(10):1486-94
pubmed: 14617750
Int J Mol Sci. 2022 Dec 28;24(1):
pubmed: 36613933
Science. 2020 Apr 24;368(6489):387-394
pubmed: 32193360
Cardiovasc Ther. 2020 Jul 21;2020:9397109
pubmed: 32821285
Curr Opin Nephrol Hypertens. 2020 Jan;29(1):4-15
pubmed: 31725015
Kidney Int Rep. 2017 Dec 08;3(3):711-721
pubmed: 29854980
Oncotarget. 2016 Oct 25;7(43):69291-69308
pubmed: 27732564
Adv Exp Med Biol. 2019;1132:99-112
pubmed: 31037629
J Ren Care. 2009 Mar;35 Suppl 1:45-50
pubmed: 19222731
Am J Med Sci. 2020 Feb;359(2):70-72
pubmed: 32039767
Am J Nephrol. 2017;46(6):501-517
pubmed: 29268247
Am J Physiol Renal Physiol. 2019 Jun 1;316(6):F1293-F1298
pubmed: 31017009
Atherosclerosis. 2019 Nov;290:59-65
pubmed: 31568963
J Pathol. 2012 Jun;227(2):175-88
pubmed: 22190171
Genome Biol. 2010;11(10):R106
pubmed: 20979621
Clin Epigenetics. 2020 Nov 11;12(1):166
pubmed: 33172487
J Am Soc Nephrol. 2003 May;14(5):1374-82
pubmed: 12707407
J Vis Exp. 2018 Aug 3;(138):
pubmed: 30124659
J Am Soc Nephrol. 2009 Jun;20(6):1179-87
pubmed: 19470685
Nature. 2010 Dec 23;468(7327):1067-73
pubmed: 20871596
Front Cell Dev Biol. 2020 Feb 28;8:123
pubmed: 32258028
Circulation. 2021 Mar 16;143(11):1157-1172
pubmed: 33720773
Am J Physiol Lung Cell Mol Physiol. 2017 Jan 1;312(1):L22-L31
pubmed: 27864286
Redox Biol. 2017 Apr;11:390-402
pubmed: 28063381
ACS Chem Biol. 2015 Aug 21;10(8):1770-7
pubmed: 26035625
Cardiovasc Diabetol. 2021 Jan 7;20(1):13
pubmed: 33413345
Nature. 2010 Dec 23;468(7327):1119-23
pubmed: 21068722
Ren Fail. 2001 May-Jul;23(3-4):471-81
pubmed: 11499562
Kidney Int. 2019 Nov;96(5):1048-1050
pubmed: 31582227
Am J Pathol. 2003 Sep;163(3):1185-92
pubmed: 12937160
Circulation. 2018 Sep 18;138(12):1236-1252
pubmed: 29653926
JAMA. 2020 Apr 28;323(16):1565-1573
pubmed: 32219359
Kidney Int. 2004 Feb;65(2):459-68
pubmed: 14717916
Clin J Am Soc Nephrol. 2021 May 8;16(5):705-716
pubmed: 33906908
Sci Rep. 2017 Aug 17;7(1):8490
pubmed: 28819200
Rheumatology (Oxford). 2007 Aug;46(8):1277-84
pubmed: 17569745
J Cell Sci. 2010 Dec 15;123(Pt 24):4195-200
pubmed: 21123617
Biochim Biophys Acta. 2013 Jul;1832(7):891-6
pubmed: 23046811
Atherosclerosis. 2016 Apr;247:48-57
pubmed: 26868508
Biomed Pharmacother. 2022 Aug;152:113230
pubmed: 35687908
Cell Signal. 2020 Aug;72:109646
pubmed: 32311505
J Am Soc Nephrol. 2003 Apr;14(4):968-80
pubmed: 12660331