Investigation of Urinary miRNA Profile Changes in Amphotericin B-Induced Nephrotoxicity in C57BL/6 Mouse, Sprague-Dawley Rats and Beagle Dogs.

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 three 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 three species. In rodents, these two 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 three nonclinical animal models.