1. Efficacy of Trametinib in Alleviating Cisplatin-Induced Acute Kidney Injury: Inhibition of Inflammation, Oxidative Stress, and Tubular Cell Death in a Mouse Model.
- Author
-
Lee JE, Kim JY, and Leem J
- Subjects
- Animals, Mice, Male, Cell Death drug effects, Apoptosis drug effects, Kidney Tubules pathology, Kidney Tubules drug effects, Kidney Tubules metabolism, Lipid Peroxidation drug effects, Cytokines metabolism, MAP Kinase Signaling System drug effects, Cisplatin adverse effects, Acute Kidney Injury chemically induced, Acute Kidney Injury drug therapy, Acute Kidney Injury metabolism, Acute Kidney Injury pathology, Pyridones pharmacology, Oxidative Stress drug effects, Pyrimidinones pharmacology, Disease Models, Animal, Inflammation drug therapy, Inflammation chemically induced, Inflammation metabolism
- Abstract
Cisplatin, a platinum-based chemotherapeutic, is effective against various solid tumors, but its use is often limited by its nephrotoxic effects. This study evaluated the protective effects of trametinib, an FDA-approved selective inhibitor of mitogen-activated protein kinase kinase 1/2 (MEK1/2), against cisplatin-induced acute kidney injury (AKI) in mice. The experimental design included four groups, control, trametinib, cisplatin, and a combination of cisplatin and trametinib, each consisting of eight mice. Cisplatin was administered intraperitoneally at a dose of 20 mg/kg to induce kidney injury, while trametinib was administered via oral gavage at 3 mg/kg daily for three days. Assessments were conducted 72 h after cisplatin administration. Our results demonstrate that trametinib significantly reduces the phosphorylation of MEK1/2 and extracellular signal-regulated kinase 1/2 (ERK1/2), mitigated renal dysfunction, and ameliorated histopathological abnormalities. Additionally, trametinib significantly decreased macrophage infiltration and the expression of pro-inflammatory cytokines in the kidneys. It also lowered lipid peroxidation by-products, restored the reduced glutathione/oxidized glutathione ratio, and downregulated NADPH oxidase 4. Furthermore, trametinib significantly inhibited both apoptosis and necroptosis in the kidneys. In conclusion, our data underscore the potential of trametinib as a therapeutic agent for cisplatin-induced AKI, highlighting its role in reducing inflammation, oxidative stress, and tubular cell death.
- Published
- 2024
- Full Text
- View/download PDF