Related Experiment Video
Updated: Jun 11, 2025
Ischemia-reperfusion Model of Acute Kidney Injury and Post Injury Fibrosis in Mice
Published on: August 9, 2013
An early and stable mouse model of polymyxin-induced acute kidney injury
Linqiong Liu1,2,3, Yuxi Liu1,2,3, Yu Xin2,3
1Departments of Critical Care Medicine, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China.
Background:
Polymyxins have been revived as a last-line therapeutic option for multi-drug resistant bacteria and continue to account for a significant proportion of global antibiotic usage. However, kidney injury is often a treatment limiting event with kidney failure rates ranging from 5 to 13%. The mechanisms underlying polymyxin-induced nephrotoxicity are currently unclear. Researches of polymyxin-associated acute kidney injury (AKI) models need to be more standardized, which is crucial for obtaining consistent and robust mechanistic results.
Methods:
In this study, male C57BL/6 mice received different doses of polymyxin B (PB) and polymyxin E (PE, also known as colistin) by different routes once daily (QD), twice daily (BID), and thrice daily (TID) for 3 days. We continuously monitored the glomerular filtration rate (GFR) and the AKI biomarkers, including serum creatinine (Scr), blood urea nitrogen (BUN), neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1). We also performed histopathological examinations to assess the extent of kidney injury.
Results:
Mice receiving PB (35 mg/kg/day subcutaneously) once daily exhibited a significant decrease in GFR and a notable increase in KIM-1 two hours after the first dose. Changes in GFR and KIM-1 at 24, 48 and 72 h were consistent and demonstrated the occurrence of kidney injury. Histopathological assessments showed a positive correlation between the severity of kidney injury and the changes in GFR and KIM-1 (Spearman's rho = 0.3167, P = 0.0264). The other groups of mice injected with PB and PE did not show significant changes in GFR and AKI biomarkers compared to the control group.
Conclusion:
The group receiving PB (35 mg/kg/day subcutaneously) once daily consistently developed AKI at 2 h after the first dose. Establishing an early and stable AKI model facilitates researches into the mechanisms of early-stage kidney injury. In addition, our results indicated that PE had less toxicity than PB and mice receiving the same dose of PB in the QD group exhibited more severe kidney injury than the BID and TID groups.
Insights
Polymyxin B (PB) at 35 mg/kg/day subcutaneously once daily caused acute kidney injury (AKI) in mice within 2 hours. Polymyxin E (PE) showed less toxicity, and less frequent PB dosing reduced AKI severity.
Area of Science:
- Nephrology
- Pharmacology
- Toxicology
Background:
- Polymyxins are crucial last-line antibiotics for multi-drug resistant bacteria.
- Polymyxin-induced nephrotoxicity is a significant clinical limitation, with kidney failure rates of 5-13%.
- Mechanisms of polymyxin nephrotoxicity and standardized AKI models require further investigation.
Purpose of the Study:
- To establish a standardized and reproducible mouse model for polymyxin-induced acute kidney injury (AKI).
- To compare the nephrotoxicity of polymyxin B (PB) and polymyxin E (PE) under different dosing regimens.
- To investigate the early onset and dose-dependency of polymyxin nephrotoxicity.
Main Methods:
- Male C57BL/6 mice received varying doses of PB and PE via different routes (QD, BID, TID) for 3 days.
- Continuous monitoring of glomerular filtration rate (GFR) and AKI biomarkers (serum creatinine, BUN, NGAL, KIM-1).
- Histopathological examination to correlate kidney injury severity with GFR and biomarker changes.
Main Results:
- Subcutaneous PB (35 mg/kg/day) once daily induced significant GFR decrease and KIM-1 elevation within 2 hours, consistent over 72 hours.
- Histopathology confirmed a positive correlation between kidney injury severity and GFR/KIM-1 changes (Spearman's rho = 0.3167, P = 0.0264).
- Other PB and PE groups showed no significant AKI biomarkers compared to controls, indicating dose and frequency dependency.
Conclusions:
- A once-daily subcutaneous PB (35 mg/kg/day) regimen reliably establishes early-stage AKI in mice.
- This model facilitates research into the mechanisms of early polymyxin-induced kidney injury.
- Polymyxin E demonstrated lower toxicity than Polymyxin B, and less frequent dosing of PB reduced AKI severity.
