The AMPK activator ATX-304 alters cellular metabolism to protect against cisplatin-induced acute kidney injury

Biomed Pharmacother. 2024 Jun:175:116730. doi: 10.1016/j.biopha.2024.116730. Epub 2024 May 14.

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; ATX-304; Acute kidney injury; Cisplatin-induced AKI; Renal energy metabolism.

MeSH terms

  • AMP-Activated Protein Kinases* / metabolism
  • Acute Kidney Injury* / chemically induced
  • Acute Kidney Injury* / metabolism
  • Acute Kidney Injury* / pathology
  • Acute Kidney Injury* / prevention & control
  • Animals
  • Biphenyl Compounds
  • Cells, Cultured
  • Cisplatin*
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL*
  • Phosphorylation
  • Protective Agents / pharmacology
  • Pyrones
  • Thiophenes

Substances

  • Cisplatin
  • AMP-Activated Protein Kinases
  • 4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile
  • Protective Agents
  • Biphenyl Compounds
  • Pyrones
  • Thiophenes