Suppressing long noncoding RNA OGRU ameliorates diabetic retinopathy by inhibition of oxidative stress and inflammation via miR-320/USP14 axis.
Long noncoding RNAs (lncRNAs) are important regulators in various diseases including diabetic retinopathy (DR). In this study, DR patients exhibited significantly increased expression of serum LncRNA-OGRU compared with normal individuals. Streptozotocin (STZ)-challenged rats with DR also had higher OGRU expression in retinas than that of the control group, which was ... confirmed in Mueller cells upon high glucose (HG) stimulation. OGRU knockdown remarkably decreased vascular endothelial growth factor (VEGF) and transforming growth factor-?1 (TGF-?1) expression in HG-incubated Mueller cells. HG-induced inflammatory response and oxidative stress in vitro were markedly mitigated by OGRU knockdown through restraining I?B?/nuclear factor kappa beta (NF-?B) and improving nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways, respectively. Further studies indicated that OGRU suppression greatly restored miR-320 expression, and a negative correlation between them was detected in DR patients. We also found that miR-320 over-expression considerably restrained TGF-?1 signaling, and hindered inflammation and reactive oxygen species (ROS) production in HG-stimulated Mueller cells. Additionally, OGRU knockdown or miR-320 over-expression could dramatically down-regulate ubiquitin-specific peptidase 14 (USP14) expression levels in HG-incubated Mueller cells, and miR-320 could directly target USP14. Notably, OGRU/miR-320 axis-mediated TGF-?1 signaling, inflammation and ROS were largely dependent on USP14. Intriguingly, our results showed that USP14 directly interacted with transforming growth factor-beta type 1 receptor (T?R1), and impeded T?R1 ubiquitination and degradation. Furthermore, USP14 could also facilitate I?B? deubiquitination and degradation, exacerbating I?B? phosphorylation and NF-?B activation. Finally, our in vivo studies confirmed that OGRU knockdown considerably ameliorated DR progression in STZ-challenged rats through mediating the mechanisms observed in vitro. Collectively, these findings implicated that LncRNA-OGRU mediated DR progression through competing for miR-320 to regulate USP14 expression, and thus LncRNA-OGRU/miR-320/USP14 axis may be considered as a therapeutic target for DR treatment.
Mesh Terms:
Animals, Diabetes Mellitus, Diabetic Retinopathy, Humans, Inflammation, MicroRNAs, Oxidative Stress, RNA, Long Noncoding, Rats, Ubiquitin Thiolesterase, Vascular Endothelial Growth Factor A
Animals, Diabetes Mellitus, Diabetic Retinopathy, Humans, Inflammation, MicroRNAs, Oxidative Stress, RNA, Long Noncoding, Rats, Ubiquitin Thiolesterase, Vascular Endothelial Growth Factor A
Free Radic Biol Med
Date: Dec. 01, 2020
PubMed ID: 33762162
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