Deletion of 12/15-Lipoxygenase Preserves Retinal Thickness and Function and Selectively Restores Dysregulated miRNAs in Experimental Diabetes Mice.

UNLABELLED: Diabetic retinopathy (DR) remains a leading cause of blindness, characterized by progressive neurovascular dysfunction. While the enzyme 12/15-lipoxygenase (12/15-LO) and its metabolites are upregulated in DR, their interactions with epigenetic regulators, such as miRNAs, are poorly understood. This study investigates the role of 12/15-LO in miRNA dysregulation and its functional consequences in a type 1 diabetic mouse model. We generated 12/15-LO knockout mice on an (Ins2+/akita) (Akita) background. Retinal miRNA expression was profiled using microarray analysis, and retinal structure and function were assessed using histology and electroretinography. Our results demonstrate that diabetes induces significant dysregulation of a distinct subset of retinal miRNAs (e.g., downregulation of miR-329-3p and miR-431-5p and upregulation of miR-3078-3p and miR-323-5p). Deletion of 12/15-LO normalized a subset of these diabetes-associated miRNA alterations and prevented retinal thinning and the loss of neuronal markers (NeuN and SCGN). Functionally, 12/15-LO deletion rescued diabetes-induced deficits in retinal ganglion cell (positive scotopic threshold response), cone bipolar cell (photopic b-wave), and cone pathway function (response to natural noise). In conclusion, our findings establish 12/15-LO as a critical upstream regulator of miRNA in the diabetic retina and demonstrate that its deletion protects against neuronal damage in DR. Thus, targeting the 12/15-LO pathway may represent a novel therapeutic strategy to mitigate neuronal dysfunction associated with DR progression.

ARTICLE HIGHLIGHTS: Retina of Akita diabetic mice demonstrated significant thinning and dysfunction. Deletion of 12/15-lipoxygenase (12/15-LO) in Akita diabetic mice, an essential enzyme that metabolizes arachidonic acid to 12- and 15-hydroxyeicosatetraenoic acids, restored normal retinal thickness and preserved retinal neurons and function. Deletion of 12/15-LO selectively restored essential mature forms of miRNA, such as miR431 and miR329, which are implicated in neuroprotection, synaptic plasticity, and cellular response to stress. Targeting 12/15-LO and its metabolites has the potential to protect retina against diabetes neurodegeneration.