The AMPK activator ATX-304 alters cellular metabolism to protect against cisplatin-induced acute kidney injury
Journal article
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, Ling, Naomi, Murray-Segal, Lisa, Brink, Robert, Lee, Mardiana, Power, David and Mount, Peter. (2024). The AMPK activator ATX-304 alters cellular metabolism to protect against cisplatin-induced acute kidney injury. Biomedicine and Pharmacotherapy. 175, pp. 116730-116742. https://doi.org/10.1016/j.biopha.2024.116730
Authors | 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, Ling, Naomi, Murray-Segal, Lisa, Brink, Robert, Lee, Mardiana, Power, David and Mount, Peter |
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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 |
Year | 01 Jan 2024 |
Journal | Biomedicine and Pharmacotherapy |
Journal citation | 175, pp. 116730-116742 |
Publisher | Elsevier Ltd. (UK) |
ISSN | 0753-3322 |
Digital Object Identifier (DOI) | https://doi.org/10.1016/j.biopha.2024.116730 |
Web address (URL) | https://www.sciencedirect.com/science/article/pii/S0753332224006140?via%3Dihub |
Open access | Open access |
Research or scholarly | Research |
Page range | 116730-116742 |
Publisher's version | License File Access Level Open |
Output status | Published |
Publication dates | |
Online | 14 May 2024 |
Publication process dates | |
Accepted | 07 May 2024 |
Deposited | 03 Sep 2024 |
Supplemental file | License File Access Level Open |
Additional information | © 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/). | |
Place of publication | France |
https://acuresearchbank.acu.edu.au/item/90xq0/the-ampk-activator-atx-304-alters-cellular-metabolism-to-protect-against-cisplatin-induced-acute-kidney-injury
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OA_Loh_2024_The_AMPK_activator_ATX_304_alters.pdf | |
License: CC BY-NC 4.0 | |
File access level: Open |
Supplemental file
SM_Loh_2024_The_AMPK_activator_ATX_304_alters.pdf | |
License: CC BY-NC 4.0 | |
File access level: Open |
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