title: Urinary microRNA profiling for identification of biomarkers after cisplatin-induced kidney injury.
abstract: Extracellular microRNAs (miRNAs) have emerged as novel biomarkers (BMs) for various pathological states. To evaluate whether urinary miRNAs could serve as biomarkers for drug-induced kidney injury, we performed a nephrotoxicity study in rats with cisplatin (Cp), which is known to induce renal proximal tubular lesions in several species. Male Wistar rats were treated with a single dose of Cp (0, 1 and 3mg/kg) and urine was collected on days 3, 5, 8, 15 and 26 for measurement of several biomarkers and for RNA isolation. MiRNA profiling experiments with urine samples derived from the 3mg/kg Cp dosed animals, identified 136 miRNAs significantly increased in urine 3 and 5 days after Cp administration. 18 miRNAs with distinct time-dependent profiles were further analyzed using specific miRNA assays and absolute quantification. We observed >20-fold changes for 11 of these 18 miRNAs measured in profiling experiments, and confirmed their direction of change and time course profile by absolute quantification. Furthermore we found mechanistic links between several miRNAs and simultaneously measured mRNAs in the kidney after Cp administration. These were associated with pathways suggested to be involved in Cp-induced nephrotoxicity including a DNA damage response, apoptosis, and cell cycle regulation. Overall our results indicate that miRNAs measured in urine may serve as BMs for nephrotoxicity in rats.
authors.affiliation: Investigational Toxicology, GDD-GED-Toxicology, Bayer Pharma AG, 42096 Wuppertal, Germany.
authors.forename: Mira
authors.initials: M
authors.lastname: Pavkovic
authors.affiliation: Investigational Toxicology, GDD-GED-Toxicology, Bayer Pharma AG, 13353 Berlin, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Riefke
authors.affiliation: Investigational Toxicology, GDD-GED-Toxicology, Bayer Pharma AG, 42096 Wuppertal, Germany. Electronic address: heidrun.ellinger-ziegelbauer@bayer.com.
authors.forename: Heidrun
authors.initials: H
authors.lastname: Ellinger-Ziegelbauer
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology / Q000652:urine*; D000818:Animals; D002945:Cisplatin; D016000:Cluster Analysis; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods*; D005819:Genetic Markers; D008297:Male; D035683:MicroRNAs / Q000652:urine*; D020411:Oligonucleotide Array Sequence Analysis; D025341:Principal Component Analysis; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D016482:Urinalysis
chemical_list: D005819:Genetic Markers; D035683:MicroRNAs; D002945:Cisplatin
keywords: Biomarker; Cisplatin; Nephrotoxicity; Urinary microRNAs