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Title: | The AMPK activator ATX-304 alters cellular metabolism to protect against cisplatin-induced acute kidney injury. | Austin Authors: | Katerelos, Marina ;Gleich, Kurt;Harley, Geoff ;Loh, Kim;Oakhill, Jonathan S;Kemp, Bruce E;de Souza, David P;Narayana, Vinod K;Coughlan, Melinda T;Laskowski, Adrienne;Ling, Naomi X Y;Murray-Segal, Lisa;Brink, Robert;Lee, Mardiana ;Power, David A ;Mount, Peter F | Affiliation: | Nephrology Institute for Breathing and Sleep St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia. St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia. St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia. Metabolomics Australia, Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Parkville, Victoria 3052, Australia. Metabolomics Australia, Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Parkville, Victoria 3052, Australia. Glycation, Nutrition and Metabolism Laboratory, Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria 3004, Australia; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University Parkville Campus, Parkville, Victoria 3052, Australia. St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia. Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia; St. Vincent's Clinical School, University of New South Wales, St. Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia. |
Issue Date: | Jun-2024 | Date: | 2024 | Publication information: | Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie 2024-06; 175 | 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. | URI: | https://ahro.austin.org.au/austinjspui/handle/1/35330 | DOI: | 10.1016/j.biopha.2024.116730 | ORCID: | Journal: | Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie | Start page: | 116730 | PubMed URL: | 38749175 | ISSN: | 1950-6007 | Type: | Journal Article | Subjects: | AMP-activated protein kinase ATX-304 Acute kidney injury Cisplatin-induced AKI Renal energy metabolism Acute Kidney Injury/chemically induced Acute Kidney Injury/prevention & control Acute Kidney Injury/metabolism Acute Kidney Injury/pathology AMP-Activated Protein Kinases/metabolism Epithelial Cells/drug effects Epithelial Cells/metabolism Protective Agents/pharmacology |
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