A scrutiny of circulating microRNA biomarkers for drug-induced tubular and glomerular injury in rats

Abstract Drug-induced acute kidney injury (AKI) is a frequent cause of adverse drug reaction. Serum creatinine (CRE) and blood urea nitrogen (BUN) are widely used as standard biomarkers for kidney injury; however, the sensitivity and specificity are considered to be low. In recent years, circulating microRNA (miRNAs) have been attracting considerable attention as novel biomarkers for organ injury, but there are currently no established miRNA biomarkers for drug-induced AKI. The present study aimed to identify plasma miRNAs that may enable early and specific detectionof drug-induced tubular and glomerular injury through next-generation sequencing analysis. Six-week old male Sprague-Dawley (SD) rats were intravenously administered cisplatin (CSP, 6 mg/kg) and gentamicin (GEN, 120 mg/kg) to induce tubular injury. To create glomerular injury models, puromycin(PUR, 120 mg/kg) and doxorubicin (DOX, 7.5 mg/kg) were intravenously administered, and these models were always accompanied by tubular damage. Small RNA-sequencing was performed to analyze time-dependent changes in the plasma miRNA profiles. The cluster analyses showed that there were distinct plasma miRNA profiles according to the types of injury, and the changes reflected the progress of renal damages. In the differential analysis, miR-3473 was specifically up-regulated in the glomerular injury models. miR-143-3p and miR-122-5p were commonly down-regulated in all models, and the changes were earlier than the traditional biomarkers, such as plasma CRE and BUN. These data indicated that changes in the specific miRNAs in plasma may enable the early and sensitive detection of tubular and glomerular injuries. The present study suggests the potential utility of plasma miRNAs in the early and type- specific detectionof drug-induced AKI.