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 (veal2gib005Δ8/+) 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.

Identification and Characterization of a Novel Long Noncoding RNA that Regulates Osteogenesis in Diet-Induced Obesity Mice

“…The functional mechanisms of lncRNAs vary; however, they can be divided into two main groups: cis -regulation and trans -transcriptional regulation ( Yan et al, 2017 ). Several lncRNAs have been discovered that affect the pathogenesis of T2D: lncRNA betaFaar regulates islet beta-cell function and survival in T2D mice; lncRNA VEAL2 targets PRKCB2 contributing to reducing hyperpermeability in a hyperglycemic animal model ( Sehgal et al, 2021 ; Zhang et al, 2021 ). This latter study suggests that lncRNA impacts the expression of genes that regulate bone mineralization.…”

Long Non Coding RNA Based Regulation of Cerebrovascular Endothelium

“…VEAL2 was found to be upregulated in the blood of diabetic retinopathy patients, and overexpression of the lncRNA in hyperglycemia model of HUVECs could attenuate PRKCB2-mediated hyper-permeability. A zebrafish knockout model for the ortholog veal2 caused cranial hemorrhage, which could be rescued by the PRKCB2 inhibitor Enzastaurin ( Sehgal et al, 2021 ). Aging related lncRNA AERRIE is important to maintain endothelial function and angiogenesis in vitro .…”

“…In lieu of the poor sequence conservation of lncRNAs, identification of lncRNAs in animal models can illuminate hitherto unknown regulatory angles in well studied pathways. Identification of functionally conserved human lncRNA has been exemplified in the case of lncRNAs jpx (mouse) ( Karner et al, 2020 ) and veal2 (zebrafish) ( Sehgal et al, 2021 ) even in the absence of sequence or structural conservation, albeit with a conserved interacting protein partner. This provides a framework to look beyond sequence-based conservation for identifying lncRNA candidates that regulate well-conserved pathways.…”

Gut Microbiota: An Important Player in Type 2 Diabetes Mellitus

“…It was reported that more than 460 million adults worldwide had diabetes in 2019, and this number would rise to 700 million by 2045 ( Saeedi et al, 2019 ). Since T2DM contributes to the occurrence of harmful macrovascular and microvascular outcomes ( Sehgal et al, 2021 ; Zeng et al, 2021 ; Zhang X. et al, 2021 ; Zhao et al, 2021 ), it not only brings physical and mental pain to patients, but also leads to a major medical economic burden. Therefore, it is of great significance to explore the novel pathogenesis and treatment of T2DM.…”