Combination of circulating microRNAs as indicators of specific targets of retinal toxicity in rats.

Circulating miR-96-5p, -124-3p, and 183-5p have been reported as safety biomarkers for retinal toxicity. In the present research, 5 serum microRNAs (miRNAs), which are highly specific to and abundant in the retina, including the 3 miRNAs previously mentioned, were assessed in 3 different models of retinal toxicity. Distinct types of retinal lesions were induced in rats by a single dose of N-methyl-N-nitrosourea (MNU: 10, 30, and 50 mg/kg, i.p.), N-methyl-d-aspartate (NMDA: 200 nmol/eye, intravitreal injection), or sodium iodate (NaIO: 30 mg/kg, i.v.). Time-course change of serum miRNAs was evaluated by RT-PCR for up to 1 week after administration. Ophthalmologic and histologic examinations and electroretinogram recording were also performed. MNU at 50 mg/kg induced photoreceptor cell death, with elevation in serum miR-96-5p, -124-3p, and -183-5p levels. NMDA induced retinal ganglion and inner nuclear layer cell death, with elevation in serum miR-124-3p. In both models, serum miRNA elevations occurred in parallel with the onset of neuroretinal cell death and retinal dysfunction. NaIO induced retinal pigment epithelial cell death without changes in neuroretinal cell or serum miRNAs. In the present research, circulating miR-124-3p was elevated in a case of retinal ganglion and inner nuclear layer cell death as well as photoreceptor cell death. Our data suggest that different patterns of circulating miRNA elevations correspond to death of a specific neuroretinal cell. A miRNA panel consisting of miR-96-5p, -124-3p, and -183-5p may be used as a biomarker to detect neuroretinal cell death and identify the specific target cell.