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The AMPK activator ATX-304 alters cellular metabolism to protect against cisplatin-induced acute kidney injury
Katerelos, Marina Gleich, Kurt Harley, Geoff Loh, Kim Oakhill, Jonathan Kemp, Bruce Ernest De Souza, David P. Narayana, Vinod K. Coughlan, Melinda T. Laskowski, Adrienne
Katerelos, Marina
Gleich, Kurt
Harley, Geoff
Loh, Kim
Oakhill, Jonathan
Kemp, Bruce Ernest
De Souza, David P.
Narayana, Vinod K.
Coughlan, Melinda T.
Laskowski, Adrienne
Abstract
Acute kidney injury (AKI) disrupts energy metabolism. Targeting metabolism through AMP-activated protein kinase (AMPK) may alleviate AKI. ATX-304, a pan-AMPK activator, was evaluated in C57Bl/6 mice and tubular epithelial cell (TEC) cultures. Mice received ATX-304 (1 mg/g) or control chow for 7 days before cisplatin-induced AKI (CI-AKI). Primary cultures of tubular epithelial cells (TECs) were pre-treated with ATX-304 (20 µM, 4 h) prior to exposure to cisplatin (20 µM, 23 h). ATX-304 increased acetyl-CoA carboxylase phosphorylation, indicating AMPK activation. It protected against CI-AKI measured by serum creatinine (control 0.05 + 0.03 mM vs ATX-304 0.02 + 0.01 mM, P = 0.03), western blot for neutrophil gelatinase-associated lipocalin (NGAL) (control 3.3 + 1.8-fold vs ATX-304 1.2 + 0.55-fold, P = 0.002), and histological injury (control 3.5 + 0.59 vs ATX-304 2.7 + 0.74, P = 0.03). In TECs, pre-treatment with ATX-304 protected against cisplatin-mediated injury, as measured by lactate dehydrogenase release, MTS cell viability, and cleaved caspase 3 expression. ATX-304 protection against cisplatin was lost in AMPK-null murine embryonic fibroblasts. Metabolomic analysis in TECs revealed that ATX-304 (20 µM, 4 h) altered 66/126 metabolites, including fatty acids, tricarboxylic acid cycle metabolites, and amino acids. Metabolic studies of live cells using the XFe96 Seahorse analyzer revealed that ATX-304 increased the basal TEC oxygen consumption rate by 38%, whereas maximal respiration was unchanged. Thus, ATX-304 protects against cisplatin-mediated kidney injury via AMPK-dependent metabolic reprogramming, revealing a promising therapeutic strategy for AKI.
Keywords
AMP-activated protein kinase, Acute kidney injury, Cisplatin-induced AKI, Renal energy metabolism, ATX-304
Date
2024
Type
Journal article
Journal
Book
Volume
175
Issue
Page Range
116730-116742
Article Number
ACU Department
Marketing and Communications
Research Office
Non-faculty
Faculty of Health Sciences
Research Office
Non-faculty
Faculty of Health Sciences
Collections
Relation URI
Event URL
Open Access Status
Published as ‘gold’ (paid) open access
License
File Access
Open
Open
Open
Notes
© 2024 The Author(s)
Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC license (http://creativecommons.org/license/by-nc/4.0/).
Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC license (http://creativecommons.org/license/by-nc/4.0/).