Blocking AMPK signalling to acetyl-CoA carboxylase increases cisplatin-induced acute kidney injury and suppresses the benefit of metformin.

AMP-Activated Protein Kinases / metabolism Acetyl-CoA Carboxylase / metabolism Acute Kidney Injury / chemically induced Animals Cisplatin / metabolism Fatty Acids Lipocalin-2 Metformin / adverse effects Mice
AMP-activated protein kinase Acetyl-CoA carboxylase Cisplatin-induced acute kidney injury Fatty acid oxidation Metabolomics Metformin Phosphorylation

Journal

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
ISSN: 1950-6007
Titre abrégé: Biomed Pharmacother
Pays: France
ID NLM: 8213295

Informations de publication

Date de publication:
Sep 2022
Historique:
received: 20 04 2022
revised: 25 06 2022
accepted: 06 07 2022
entrez: 9 9 2022
pubmed: 10 9 2022
medline: 14 9 2022
Statut: ppublish

Résumé

Acute kidney injury (AKI) is accompanied by dysregulation of cellular energy metabolism and accumulation of intracellular lipid. Phosphorylation of acetyl-CoA carboxylase (ACC) by AMP-activated protein kinase (AMPK) inhibits fatty acid synthesis and promotes fatty acid oxidation (FAO), vital for kidney tubular epithelial cells (TECs). The diabetes drug metformin is protective in models of AKI; however, it is not known whether ACC phosphorylation plays a role. Cisplatin-induced AKI (CI-AKI) was established in ACC1/2 double knock-in (ACC1/2DKI) mice, harbouring mutations that disrupt fatty acid metabolism, and the role of metformin was studied in this model. Outcomes measured included serum biochemistry, expression of kidney injury markers such as neutrophil gelatinase-associated lipocalin (NGAL), and metabolomic analysis. ACC1/2DKI mice demonstrated more severe CI-AKI than wild type (WT), as assessed by serum urea and creatinine, histological injury, and expression of NGAL and interleukin-6. Metformin protected against AKI in WT mice, shown by reduced NGAL, but this effect was absent in ACC1/2DKI mice. In cultured TECs exposed to cisplatin, metformin reduced expression of cleaved caspase-3, however, this effect was diminished in ACC1/2DKI TECs. Analysis of kidney polar metabolites found numerous differences between metformin-treated CI-AKI in ACC1/2DKI and WT mice, involving multiple pathways of amino acid, nucleoside, and energy metabolism. Severity of CI-AKI is exacerbated by the inability to regulate metabolism via phosphorylation of ACC. ACC phosphorylation contributes to the protective effect of metformin against AKI, influencing multiple mechanisms involved in the pathogenesis of kidney injury.

Sections du résumé

BACKGROUND BACKGROUND
Acute kidney injury (AKI) is accompanied by dysregulation of cellular energy metabolism and accumulation of intracellular lipid. Phosphorylation of acetyl-CoA carboxylase (ACC) by AMP-activated protein kinase (AMPK) inhibits fatty acid synthesis and promotes fatty acid oxidation (FAO), vital for kidney tubular epithelial cells (TECs). The diabetes drug metformin is protective in models of AKI; however, it is not known whether ACC phosphorylation plays a role.
METHODS METHODS
Cisplatin-induced AKI (CI-AKI) was established in ACC1/2 double knock-in (ACC1/2DKI) mice, harbouring mutations that disrupt fatty acid metabolism, and the role of metformin was studied in this model. Outcomes measured included serum biochemistry, expression of kidney injury markers such as neutrophil gelatinase-associated lipocalin (NGAL), and metabolomic analysis.
FINDINGS RESULTS
ACC1/2DKI mice demonstrated more severe CI-AKI than wild type (WT), as assessed by serum urea and creatinine, histological injury, and expression of NGAL and interleukin-6. Metformin protected against AKI in WT mice, shown by reduced NGAL, but this effect was absent in ACC1/2DKI mice. In cultured TECs exposed to cisplatin, metformin reduced expression of cleaved caspase-3, however, this effect was diminished in ACC1/2DKI TECs. Analysis of kidney polar metabolites found numerous differences between metformin-treated CI-AKI in ACC1/2DKI and WT mice, involving multiple pathways of amino acid, nucleoside, and energy metabolism.
INTERPRETATION CONCLUSIONS
Severity of CI-AKI is exacerbated by the inability to regulate metabolism via phosphorylation of ACC. ACC phosphorylation contributes to the protective effect of metformin against AKI, influencing multiple mechanisms involved in the pathogenesis of kidney injury.

Identifiants

DOI: 10.1016/j.biopha.2022.113377 PMID: 36076520
pubmed: 36076520
pii: S0753-3322(22)00766-1
doi: 10.1016/j.biopha.2022.113377
pii:
doi:

Substances chimiques

Fatty Acids 0
Lipocalin-2 0
Metformin 9100L32L2N
AMP-Activated Protein Kinases EC 2.7.11.31
Acetyl-CoA Carboxylase EC 6.4.1.2
Cisplatin Q20Q21Q62J

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

113377

Informations de copyright

Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Déclaration de conflit d'intérêts

Conflict of interest statement The authors have no conflicts of interest to declare in relation to this manuscript.

Auteurs

Geoff Harley (G)

Department of Medicine, The University of Melbourne, Heidelberg, VIC, Australia; Kidney Laboratory, The Institute for Breathing and Sleep (IBAS), Austin Health, Heidelberg, VIC, Australia.

Marina Katerelos (M)

Kidney Laboratory, The Institute for Breathing and Sleep (IBAS), Austin Health, Heidelberg, VIC, Australia; Department of Nephrology, Austin Health, Heidelberg, VIC 3084, Australia.

Kurt Gleich (K)

Kidney Laboratory, The Institute for Breathing and Sleep (IBAS), Austin Health, Heidelberg, VIC, Australia; Department of Nephrology, Austin Health, Heidelberg, VIC 3084, Australia.

David P de Souza (DP)

Metabolomics Australia, Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Melbourne, Australia.

Vinod K Narayana (VK)

Metabolomics Australia, Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Melbourne, Australia.

Bruce E Kemp (BE)

Department of Medicine, University of Melbourne, Melbourne, Australia; Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia; Protein Chemistry and Metabolism, St. Vincent's Institute of Medical Research, Fitzroy, Australia, University of Melbourne, Melbourne, Australia.

David A Power (DA)

Department of Medicine, The University of Melbourne, Heidelberg, VIC, Australia; Kidney Laboratory, The Institute for Breathing and Sleep (IBAS), Austin Health, Heidelberg, VIC, Australia; Department of Nephrology, Austin Health, Heidelberg, VIC 3084, Australia.

Peter F Mount (PF)

Department of Medicine, The University of Melbourne, Heidelberg, VIC, Australia; Kidney Laboratory, The Institute for Breathing and Sleep (IBAS), Austin Health, Heidelberg, VIC, Australia; Department of Nephrology, Austin Health, Heidelberg, VIC 3084, Australia. Electronic address: Peter.Mount@austin.org.au.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › AMP-Activated Protein Kinases › Blocking AMPK signalling to acetyl-CoA...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Enzymes multifonctionnelles › Acetyl-coA carboxylase › Blocking AMPK signalling to acetyl-CoA...
questionsmedicales.fr › Maladies urogénitales › Maladies urologiques › Maladies du rein › Insuffisance rénale › Atteinte rénale aigüe › Blocking AMPK signalling to acetyl-CoA...
questionsmedicales.fr › Eucaryotes › Animaux › Blocking AMPK signalling to acetyl-CoA...
questionsmedicales.fr › Produits chimiques inorganiques › Composés du platine › Cisplatine › Blocking AMPK signalling to acetyl-CoA...
questionsmedicales.fr › Lipides › Acides gras › Blocking AMPK signalling to acetyl-CoA...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines proto-oncogènes › Lipocaline-2 › Blocking AMPK signalling to acetyl-CoA...
questionsmedicales.fr › Composés chimiques organiques › Amidines › Guanidines › Biguanides › Metformine › Blocking AMPK signalling to acetyl-CoA...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Blocking AMPK signalling to acetyl-CoA...