%0 Journal Article
%T Mechanistic Insights Into Vancomycin-Induced Renal Injury: The Role of Ferroptosis and GPX4 Suppression
%A Gabriel Johansen
%A Ingrid Solheim
%J Pharmaceutical Sciences and Drug Design
%@ 3062-4428
%D 2024
%V 4
%N 1
%R 10.51847/EOpAdGArpc
%P 128-140
%X Vancomycin (VCM) is commonly used to treat infections caused by Gram-positive bacteria. However, over the past decades, VCM overdose has increasingly been linked to kidney damage. The mechanisms driving this nephrotoxicity remain incompletely understood. This study aimed to investigate how VCM induces renal injury.Kidney tissues from mice were analyzed for the expression of Ki67, DDX5, PTGS2, GPX4, and SLC7A11 using immunohistochemistry, RT-qPCR, and Western blot. In parallel, HK-2 cells were assessed for viability and apoptosis via CCK-8 and flow cytometry. Additional assays measured ACSL4, PTGS2, GPX4, SLC7A11, DDX5, and Ki67 expression in HK-2 cells at the mRNA and protein levels.VCM triggered ferroptotic cell death in both HK-2 cells and mouse kidney tissues. Application of Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, restored cell survival and improved renal structure and function in VCM-exposed models. VCM treatment reduced GPX4 levels, a critical enzyme that prevents lipid peroxidation and ferroptosis. Notably, knocking down GPX4 in HK-2 cells recapitulated VCM-induced changes, including upregulation of ACSL4, PTGS2, DDX5, and Ki67, suggesting that GPX4 suppression mediates VCM-triggered ferroptosis.These results demonstrate that VCM-induced kidney injury involves ferroptosis driven by GPX4 downregulation and accumulation of lipid peroxides. This study provides new mechanistic insight into VCM nephrotoxicity and may guide safer therapeutic strategies for its clinical use.
%U https://galaxypub.co/article/mechanistic-insights-into-vancomycin-induced-renal-injury-the-role-of-ferroptosis-and-gpx4-suppress-dyzzamtxzrcddob