Regulation of endothelin receptor expression by microRNAs in diabetes related erectile dysfunction

Erectile dysfunction (ED) is one of the common complications of type 2 diabetes mellitus (T2DM), feathered by a complex vascular and endothelial pathogenesis and limited therapeutic options. Endothelin receptor type A (ETA), a key receptor for endothelin, mediates chronic and persistent contractile effects in the penile corpus cavernosum (CC), and is a potential target for ED treatment. Dysregulated microRNAs (miRNAs) have been implicated in the pathophysiology of ED, playing critical regulatory roles and suitable for drug development. This study investigates the role of dysregulated miRNAs in regulating the endothelin receptor type A gene (EDNRA) in T2DMED. We found that ETA levels were significantly higher in the CCs of T2DMED rats. Using artificial intelligence (AI)-assisted prediction algorithms, potential miRNAs targeting EDNRA were identified, and miRNA expression profiles in the CCs of control and T2DMED rats were analyzed using RNA-chip technology and testified by quantitative Polymerase Chain Reaction (qPCR). As a result, miR-30-5p and its families, miR-96-5p, and miR-27a-3p were significantly downregulated in the T2DMED group. Luciferase assays confirmed the inhibitory role of these miRNAs on the 3'-untranslated region (3'-UTR) of EDNRA. Hypoxia, a fundamental pathogenic factor in T2DMED, was shown to suppress miRNA expression and increase ETA expression in vitro in penile smooth muscle cells. Additionally, local lentiviral delivery of miR-30-5p in vivo significantly reduced ETA levels in the CCs of T2DMED rats and restored erectile function. In conclusion, downregulated miRNAs contribute to T2DMED pathogenesis by upregulating ETA expression. Targeting EDNRA-regulating miRNAs could offer a novel therapeutic approach for T2DMED.