Axl-inhibitor bemcentinib alleviates mitochondrial dysfunction in the unilateral ureter obstruction murine model.
Animals
Benzocycloheptenes
/ pharmacology
Citric Acid Cycle
Fatty Acids
/ metabolism
Male
Mice
Mice, Inbred C57BL
Mitochondria
/ drug effects
Oxidative Phosphorylation
Phosphatidylinositol 3-Kinases
/ metabolism
Protein Kinase Inhibitors
/ pharmacology
Proto-Oncogene Proteins
/ antagonists & inhibitors
Proto-Oncogene Proteins c-akt
/ metabolism
Reactive Oxygen Species
/ metabolism
Receptor Protein-Tyrosine Kinases
/ antagonists & inhibitors
Renal Insufficiency, Chronic
/ drug therapy
Triazoles
/ pharmacology
Ureteral Obstruction
/ complications
Axl Receptor Tyrosine Kinase
AXL inhibition
UUO model
bemcentinib
mitochondria
oxidative stress
renal fibrosis
Journal
Journal of cellular and molecular medicine
ISSN: 1582-4934
Titre abrégé: J Cell Mol Med
Pays: England
ID NLM: 101083777
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
revised:
04
06
2021
received:
25
02
2021
accepted:
18
06
2021
pubmed:
6
7
2021
medline:
3
2
2022
entrez:
5
7
2021
Statut:
ppublish
Résumé
Renal fibrosis is a progressive histological manifestation leading to chronic kidney disease (CKD) and associated with mitochondrial dysfunction. In previous work, we showed that Bemcentinib, an Axl receptor tyrosine kinase inhibitor, reduced fibrosis development. In this study, to investigate its effects on mitochondrial dysfunction in renal fibrosis, we analysed genome-wide transcriptomics data from a unilateral ureter obstruction (UUO) murine model in the presence or absence of bemcentinib (n = 6 per group) and SHAM-operated (n = 4) mice. Kidney ligation resulted in dysregulation of mitochondria-related pathways, with a significant reduction in the expression of oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), citric acid cycle (TCA), response to reactive oxygen species and amino acid metabolism-related genes. Bemcentinib treatment increased the expression of these genes. In contrast, AKT/PI3K signalling pathway genes were up-regulated upon UUO, but bemcentinib largely inhibited their expression. At the functional level, ligation reduced mitochondrial biomass, which was increased upon bemcentinib treatment. Serum metabolomics analysis also showed a normalizing amino acid profile in UUO, compared with SHAM-operated mice following bemcentinib treatment. Our data suggest that mitochondria and mitochondria-related pathways are dramatically affected by UUO surgery and treatment with Axl-inhibitor bemcentinib partially reverses these effects.
Identifiants
pubmed: 34219376
doi: 10.1111/jcmm.16769
pmc: PMC8335678
doi:
Substances chimiques
Benzocycloheptenes
0
Fatty Acids
0
Protein Kinase Inhibitors
0
Proto-Oncogene Proteins
0
Reactive Oxygen Species
0
Triazoles
0
bemcentinib
0ICW2LX8AS
Receptor Protein-Tyrosine Kinases
EC 2.7.10.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Axl Receptor Tyrosine Kinase
0
AXL receptor tyrosine kinase, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7407-7417Informations de copyright
© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.
Références
Biomolecules. 2019 Apr 08;9(4):
pubmed: 30965656
Nat Med. 2015 Jan;21(1):37-46
pubmed: 25419705
Cell. 2016 Jul 28;166(3):555-566
pubmed: 27471965
J Ethnopharmacol. 2020 Jul 15;257:112858
pubmed: 32278030
Chem Biol Interact. 2018 Dec 25;296:229-239
pubmed: 30339777
Mol Cancer. 2019 Nov 4;18(1):153
pubmed: 31684958
Cell Metab. 2019 Oct 1;30(4):784-799.e5
pubmed: 31474566
Metabolism. 2012 Nov;61(11):1495-511
pubmed: 22921946
Semin Nephrol. 2016 Nov;36(6):436-447
pubmed: 27987541
Mediators Inflamm. 2017;2017:8316560
pubmed: 28348462
BMC Genomics. 2009 Aug 21;10:388
pubmed: 19698090
Front Pharmacol. 2016 Sep 15;7:307
pubmed: 27695416
Physiol Rep. 2016 May;4(9):
pubmed: 27162261
Nat Cell Biol. 2018 Jul;20(7):745-754
pubmed: 29950572
Int J Mol Sci. 2015 Sep 07;16(9):21486-519
pubmed: 26370974
Sci Rep. 2019 Jun 12;9(1):8545
pubmed: 31189949
Biomed Pharmacother. 2013 Jul;67(6):481-7
pubmed: 23773853
J Am Soc Nephrol. 2003 Jun;14(6):1535-48
pubmed: 12761254
Nat Rev Drug Discov. 2016 Aug;15(8):568-88
pubmed: 27230798
OMICS. 2012 May;16(5):284-7
pubmed: 22455463
J Biol Chem. 2013 Dec 6;288(49):35387-95
pubmed: 24142790
Curr Pathobiol Rep. 2013 Sep;1(3):
pubmed: 24386614
Br J Cancer. 2017 Feb 14;116(4):415-423
pubmed: 28072762
Biomed Pharmacother. 2021 Jan;133:111003
pubmed: 33227702
Nat Genet. 2000 May;25(1):25-9
pubmed: 10802651
Eur J Nutr. 2021 Feb;60(1):529-544
pubmed: 32409916
Sci Rep. 2016 Jun 03;6:27194
pubmed: 27256510
Nat Rev Nephrol. 2018 May;14(5):291-312
pubmed: 29456246
Am J Kidney Dis. 2014 May;63(5):771-80
pubmed: 24315119
Bioinformatics. 2016 Sep 15;32(18):2847-9
pubmed: 27207943
Proc Natl Acad Sci U S A. 2011 Jan 4;108(1):91-6
pubmed: 21173275
EBioMedicine. 2017 Dec;26:68-77
pubmed: 29128444
PLoS One. 2019 Jun 28;14(6):e0218986
pubmed: 31251767
Am J Physiol Renal Physiol. 2004 Dec;287(6):F1283-93
pubmed: 15328069
Physiol Rep. 2019 May;7(10):e14091
pubmed: 31134766
Lancet. 2020 Feb 29;395(10225):709-733
pubmed: 32061315
Biofactors. 2020 Sep;46(5):716-733
pubmed: 32905648
Kidney Int. 2012 Dec;82(12):1271-83
pubmed: 22854643
J Am Soc Nephrol. 2018 Apr;29(4):1223-1237
pubmed: 29440279
Nutr Metab (Lond). 2015 Nov 25;12:49
pubmed: 26612997
Aging Cell. 2019 Oct;18(5):e13004
pubmed: 31318148
PLoS One. 2014 Jan 20;9(1):e85445
pubmed: 24465563
Nephrol Dial Transplant. 2017 Jul 1;32(7):1154-1166
pubmed: 28339984
Am J Clin Nutr. 2004 Feb;79(2):185-97
pubmed: 14749222
Transl Res. 2018 Dec;202:1-23
pubmed: 30036495
J Cell Mol Med. 2021 Aug;25(15):7407-7417
pubmed: 34219376
Kidney Int. 2009 Jun;75(11):1145-1152
pubmed: 19340094
Am J Physiol Renal Physiol. 2013 Aug 15;305(4):F520-31
pubmed: 23761667