Language
English
Publication Date
7-1-2024
Journal
American Journal of Physiology-Renal Physiology
DOI
10.1152/ajprenal.00029.2024
PMID
38779756
PMCID
PMC12180518
PubMedCentral® Posted Date
5-23-2024
PubMedCentral® Full Text Version
Post-print
Abstract
Polymyxins are a last-resort treatment option for multidrug-resistant gram-negative bacterial infections, but they are associated with nephrotoxicity. Gelofusine was previously shown to reduce polymyxin-associated kidney injury in an animal model. However, the mechanism(s) of renal protection has not been fully elucidated. Here, we report the use of a cell culture model to provide insights into the mechanisms of renal protection. Murine epithelial proximal tubular cells were exposed to polymyxin B. Cell viability, lactate dehydrogenase (LDH) release, polymyxin B uptake, mitochondrial superoxide production, nuclear morphology, and apoptosis activation were evaluated with or without concomitant gelofusine. A megalin knockout cell line was used as an uptake inhibition control. Methionine was included in selected experiments as an antioxidant control. A polymyxin B concentration-dependent reduction in cell viability was observed. Increased viability was observed in megalin knockout cells following comparable polymyxin B exposures. Compared with polymyxin B exposure alone, concomitant gelofusine significantly increased cell viability as well as reduced LDH release, polymyxin B uptake, mitochondrial superoxide, and apoptosis. Gelofusine and methionine were more effective at reducing renal cell injury in combination than either agent alone. In conclusion, the mechanisms of renal protection by gelofusine involve decreasing cellular drug uptake, reducing subsequent oxidative stress and apoptosis activation. These findings would be valuable for translational research into clinical strategies to attenuate drug-associated acute kidney injury.
Keywords
Animals, Polymyxin B, Mice, Apoptosis, Anti-Bacterial Agents, Cell Survival, Kidney Tubules, Proximal, Cell Line, Low Density Lipoprotein Receptor-Related Protein-2, Acute Kidney Injury, Oxidative Stress, L-Lactate Dehydrogenase, antibiotic-associated nephrotoxicity, megalin, nephroprotective compounds, proximal tubule, translational research
Published Open-Access
yes
Recommended Citation
Hudson, Cole S; Roy, Anirban; Li, Qingtian; et al., "Mechanisms of Gelofusine Protection in an In Vitro Model of Polymyxin B-associated Renal Injury" (2024). Faculty and Staff Publications. 4731.
https://digitalcommons.library.tmc.edu/baylor_docs/4731
Graphical Abstract