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Title: Blocking AMPK signalling to acetyl-CoA carboxylase increases cisplatin-induced acute kidney injury and suppresses the benefit of metformin.
Austin Authors: Harley, Geoff ;Katerelos, Marina ;Gleich, Kurt;de Souza, David P;Narayana, Vinod K;Kemp, Bruce E;Power, David A ;Mount, Peter F 
Affiliation: Protein Chemistry and Metabolism, St. Vincent's Institute of Medical Research, Fitzroy, Australia, University of Melbourne, Melbourne, Australia
General Medicine
Department of Medicine, University of Melbourne, Melbourne, Australia
Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia
Metabolomics Australia, Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Melbourne, Australia
Medicine (University of Melbourne)
Institute for Breathing and Sleep
Issue Date: 1-Sep-2022
Date: 2022
Publication information: Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie 2022; 153: 113377
Abstract: 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.
DOI: 10.1016/j.biopha.2022.113377
Journal: Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie
PubMed URL: 36076520
Type: Journal Article
Subjects: AMP-activated protein kinase
Acetyl-CoA carboxylase
Cisplatin-induced acute kidney injury
Fatty acid oxidation
Appears in Collections:Journal articles

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