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A Quantitative Detection Method for MicroRNAs in the Kidney of an Ischemic Kidney Injury Mouse Model
Published on: September 11, 2020
Investigation of urinary miRNA profile changes in amphotericin B-induced nephrotoxicity in C57BL/6 mouse,
Adeyemi O Adedeji1, Michael R Tackett2, Genesis Tejada2
1Genentech, A Member of the Roche Group, South San Francisco, CA 94080, United States.
Abstract:
MicroRNA (miRNAs) have been associated with drug-induced kidney injury (DIKI). However, there are few reports on the utility of miRNAs, when monitoring for nephrotoxicity across multiple species. The purpose of this study was to assess the value of urinary miRNA profile changes as renal safety biomarkers, when monitoring for kidney injury in investigative toxicology studies. To this end, we evaluated urine miRNA expression levels in response to amphotericin B (AmpB)-induced nephrotoxicity in mice, rats, and dogs. The results showed that 35 miRNAs were significantly differentially expressed across the 3 species in response to the induced renal injuries. Dogs showed the highest number of miRNAs with significant changes. miR-205-5p and miR-31-5p were the most consistently altered miRNA biomarkers across all 3 species. In rodents, these 2 miRNAs were the most sensitive markers and showed comparable or better sensitivities than the previously published urine protein biomarkers with the same nephrotoxicant. In dogs, none of the upregulated miRNAs were as sensitive as urine clusterin protein as observed in a previously published study with AmpB. Taken together, these miRNAs could complement the more established urinary protein biomarkers in monitoring DIKI in mice, rats, and dogs. To our knowledge, this is the first report that demonstrates the comparative utility of urinary miRNAs for the early detection of DIKI across 3 nonclinical animal models.
Insights
Urinary microRNAs (miRNAs) show promise as biomarkers for detecting drug-induced kidney injury (DIKI) across mice, rats, and dogs. These novel biomarkers offer a sensitive method for monitoring nephrotoxicity in toxicology studies.
Area of Science:
- Toxicology
- Biomarkers
- Molecular Biology
Background:
- MicroRNAs (miRNAs) are implicated in drug-induced kidney injury (DIKI).
- Limited data exists on using miRNAs for cross-species nephrotoxicity monitoring.
- Urinary miRNA profiles are underexplored as safety biomarkers in toxicology.
Purpose of the Study:
- To evaluate urinary miRNA expression changes as biomarkers for kidney injury in toxicology.
- To assess the utility of miRNAs for monitoring nephrotoxicity across multiple species.
- To compare miRNA biomarker sensitivity against established protein biomarkers.
Main Methods:
- Induced nephrotoxicity using amphotericin B (AmpB) in mice, rats, and dogs.
- Analyzed urine miRNA expression levels in response to AmpB.
- Compared differential miRNA expression across species and with protein biomarkers.
Main Results:
- 35 miRNAs were significantly altered across all three species following induced kidney injury.
- miR-205-5p and miR-31-5p were consistently altered biomarkers in mice, rats, and dogs.
- In rodents, these miRNAs showed sensitivity comparable or superior to protein biomarkers; in dogs, they were less sensitive than urinary clusterin.
Conclusions:
- Urinary miRNAs can serve as valuable biomarkers for detecting drug-induced kidney injury (DIKI) in mice, rats, and dogs.
- These miRNAs may complement existing urinary protein biomarkers for enhanced nephrotoxicity monitoring.
- This study provides the first comparative analysis of urinary miRNA utility for DIKI detection across three nonclinical species.
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