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LncRNA VEAL2 regulates PRKCB2 to modulate endothelial permeability in diabetic retinopathy.

ABSTRACT: Long non-coding RNAs (lncRNAs) are emerging as key regulators of endothelial cell function. Here, we investigated the role of a novel vascular endothelial-associated lncRNA (VEAL2) in regulating endothelial permeability. Precise editing of veal2 loci in zebrafish (veal2^gib005Δ8/+ ) induced cranial hemorrhage. In vitro and in vivo studies revealed that veal2 competes with diacylglycerol for interaction with protein kinase C beta-b (Prkcbb) and regulates its kinase activity. Using PRKCB2 as bait, we identified functional ortholog of veal2 in humans from HUVECs and named it as VEAL2. Overexpression and knockdown of VEAL2 affected tubulogenesis and permeability in HUVECs. VEAL2 was differentially expressed in choroid tissue in eye and blood from patients with diabetic retinopathy, a disease where PRKCB2 is known to be hyperactivated. Further, VEAL2 could rescue the effects of PRKCB2-mediated turnover of endothelial junctional proteins thus reducing hyperpermeability in hyperglycemic HUVEC model of diabetic retinopathy. Based on evidence from zebrafish and hyperglycemic HUVEC models and diabetic retinopathy patients, we report a hitherto unknown VEAL2 lncRNA-mediated regulation of PRKCB2, for modulating junctional dynamics and maintenance of endothelial permeability.

SUBMITTER: Sehgal P

PROVIDER: S-EPMC8327952 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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LncRNA VEAL2 regulates PRKCB2 to modulate endothelial permeability in diabetic retinopathy.

Sehgal Paras P Mathew Samatha S Sivadas Ambily A Ray Arjun A Tanwar Jyoti J Vishwakarma Sushma S Ranjan Gyan G Shamsudheen K V KV Bhoyar Rahul C RC Pateria Abhishek A Leonard Elvin E Lalwani Mukesh M Vats Archana A Pappuru Rajeev R RR Tyagi Mudit M Jakati Saumya S Sengupta Shantanu S B K Binukumar B Chakrabarti Subhabrata S Kaur Inderjeet I Motiani Rajender K RK Scaria Vinod V Sivasubbu Sridhar S

The EMBO journal 20210628 15

Long non-coding RNAs (lncRNAs) are emerging as key regulators of endothelial cell function. Here, we investigated the role of a novel vascular endothelial-associated lncRNA (VEAL2) in regulating endothelial permeability. Precise editing of veal2 loci in zebrafish (veal2<sup>gib005Δ8/+</sup> ) induced cranial hemorrhage. In vitro and in vivo studies revealed that veal2 competes with diacylglycerol for interaction with protein kinase C beta-b (Prkcbb) and regulates its kinase activity. Using PRKCB ...[more]

PMID: 34180064

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Project description:ObjectiveDiabetic retinopathy (DR) is a common complication of diabetes, and recent findings have shown that long noncoding RNAs (lncRNAs) may be involved in its pathogenesis. Through bioinformatics analysis, we found that lncRNA ATP2B2-IT2 may be involved in this process. This study primarily investigated the expression of the lncRNA ATP2B2-IT2 in human retinal microvascular endothelial cells (HRMECs) under high-glucose conditions and its effects on HRMEC proliferation, migration, and neovascularization.MethodsWe used RT‒PCR to assess the expression levels of lncRNA ATP2B2-IT2 and vascular endothelial growth factor (VEGF) in HRMECs under normal glucose (5.5 mmol/L) and high glucose (30 mmol/L) conditions. HRMECs were subsequently divided into four groups: the normal glucose (NG), high glucose (HG), high glucose with lncRNA ATP2B2-IT2 silencing (HG + si-lncRNA ATP2B2-IT2), and high glucose with silencing control (HG + si-NC) groups. The expression levels of the lncRNA ATP2B2-IT2 and VEGF in each group were determined using RT‒PCR. Thereafter, cell proliferation, migration, and neovascularization were assessed using CCK-8, Transwell, and tube formation assays, respectively.ResultsRT‒PCR revealed that the expression levels of the lncRNA ATP2B2-IT2 and VEGF were greater in the HG group than in the NG group (P < 0.05). After silencing of the lncRNA ATP2B2-IT2, the expression of VEGF decreased significantly (P < 0.05). Subsequent CCK-8, Transwell, and tube formation assays demonstrated that compared to those in the NG group, the HRMECs in the HG group exhibited significantly increased proliferation, migration, and neovascularization (P < 0.05). However, after silencing of the lncRNA ATP2B2-IT2, the proliferation, migration, and neovascularization of HRMECs were significantly decreased in the HG + si-lncRNA ATP2B2-IT2 group compared to those in the HG group (P < 0.05).ConclusionLncRNA ATP2B2-IT2 may promote the proliferation, migration and neovascularization of HRMECs under high-glucose conditions.

Project description:IntroductionDiabetic retinopathy (DR) is the most common complication of diabetes. Neuronal apoptosis, activated microglia, and microvascular changes are early features of DR. The gut microbiota is critical for the maturation and activation of microglia in the brain, and DR patients exhibit gut dysbiosis. However, the effect of the gut microbiota on retinal microglia under normal or diabetic conditions is still unclear.MethodsType 2 diabetes (T2D) was established in male adult Brown Norway (BN) rats, and they were treated with gavage of broad-spectrum antibiotic (ABX) suspension. Retinal fundus fluorescein angiography was performed to observe the dynamic growth process and leakage of blood vessels. Retro-orbital injection of FITC-Dextran was performed to observe the changes in blood-retinal barriers. After treatment with ABX and diabetes lasting for more than 6 months, 16S RNA sequencing of stool samples was performed to determine changes in the gut microbiome and mass spectrometry was used to analyze metabolome changes. IBA1, IB4, and Brn3 staining were performed on adult rats' retinal wholemount or sections to observe the changes in microglia, blood vessels and the number of ganglion cells.ResultsLong-term (6 months) T2D caused gut dysbiosis with increased average taxa numbers. We showed that broad-spectrum antibiotics (ABXs) gavage can reduce the average number of gut microbiota taxa and retinal microglia in adult male BN rats with or without T2D. Interestingly, adult male BN rats with T2D for more than 6 months showed a loss of retinal ganglion cells (RGCs) without significant changes in retinal microglia or retinal vascular vessels. However, ABX gavage reduced retinal microglia and alleviated RGC damage in these T2D rats.ConclusionOur data suggests that ABX gavage-induced gut dysbiosis can reduce retinal microglia in adult rats and alleviate RGC loss in long-term T2D rats. Targeting the gut microbiota may be a future therapeutic strategy for DR management.

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LncRNA VEAL2 regulates PRKCB2 to modulate endothelial permeability in diabetic retinopathy.

Publications

LncRNA VEAL2 regulates PRKCB2 to modulate endothelial permeability in diabetic retinopathy.

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