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MiR-486-5p inhibits eNOS and angiogenesis in cultured endothelial cells by targeting MAML3

ABSTRACT: Kidney ischemia-reperfusion injury (IR) is associated with endothelial injury. Administration of miR-486-5p protects against rat kidney IR injury, with localization to capillary endothelial cells, although it inhibits IR-induced endothelial nitric oxide synthase (eNOS) protein expression. We studied the effects of miR-486-5p on eNOS and endothelial cell function and determined its mRNA targets. Methods: Human umbilical vein endothelial cells (HUVECs) were transfected with miR-486-5p and assayed for proliferation, migrartion, and network formation. Biotinylated miR-486-5p was transfected for pull-down of bound mRNA, followed by RNA sequencing. Results: miR-486-5p markedly decreased eNOS mRNA and protein in HUVECs, although eNOS mRNA was not found to be a direct target of miR-486-5p. miR-486-5p inhibited angiogenesis, which was rescued with eNOS plasmid transfection. RNA sequencing of biotinylated miR-486-5p pull-down RNA revealed highly significant enrichmenet in predicted targets FOXO1, FOXP1, TNFSF4, MAML3, and CELSR3, and in the non-predicted target SPCS2. RT-qPCR validated these transcripts as inhibited miR-486-5p. While silencing of FOXO1 had no impact on eNOS protein, MAML3 silencing inhibited eNOS levels. Conclusion: miR-486-5p inhibits angiogenesis in endothelial cells via down-regulation of eNOS, which involves selective targeting of MAML3. These data support a novel pathway regulating endothelial cell function.

ORGANISM(S): Homo sapiens

PROVIDER: GSE281065 | GEO | 2025/06/04

REPOSITORIES: GEO

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Project description:Background: Acute kidney injury (AKI) is a common clinical event with high morbidity and mortality. We previously demonstrated that injection of cord blood endothelial colony forming cell (ECFC)-derived exosomes, highly enriched in miRNA(miR)-486-5p, prevented ischemic kidney injury in mice. While preclinical models support involvement of several miRs in AKI, the direct effects of miR-486-5p on injury and the kidney transcriptome are unknown. Objective: We studied effects of miR-486-5p in mice with kidney ischemia-reperfusion (IR) injury, and compared the impact of miR-486-5p and ECFC-derived exosomes on the transcriptome of proximal tubules (PTs) and renal endothelial cells. Methods: Adult male mice were subjected to bilateral kidney ischemia (30 min), and injected via tail vein with or without vehicle, miR-486-5p mimic, ECFC-derived exosomes, or scramble miR at the start of reperfusion. Plasma and tissues were collected 24 hrs after reperfusion, and proximal tubular and endothelial cells were isolated for mRNA analysis by RNA-Seq. Results: In mice with kidney IR, injection of miR-486-5p mimic increased levels of miR-486-5p in proximal tubules and endothelial cells, and significantly improved plasma creatinine, histological injury, neutrophil infiltration, and apoptosis, compared to vehicle treatment. MiR-486-5p inhibited expression of phosphatase and tensin homolog (PTEN), and activated AKT. Similar results were observed with exosomes, but scramble miR had no effect. In proximal tubules, miR-486-5p or exosomes reduced expression of several AKI genes (e.g. Lcn2, Havcr1 and Krt20) and caused alterations in apoptotic genes compared to IR alone. In endothelium, miR-486-5p or exosomes caused milder effect than in PTs but still impacting on expression of injury-related genes. Conclusion: MiR-486-5p protects mice against ischemic kidney injury. Both miR-486-5p and exosomes reduce expression of apoptotic genes in PTs and endothelium. The results suggest that systemic delivery of miR-486-5p has therapeutic potential in ischemic AKI.

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MiR-486-5p inhibits eNOS and angiogenesis in cultured endothelial cells by targeting MAML3

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