LncRNA VEAL2 regulates PRKCB2 to modulate endothelial permeability in diabetic retinopathy
Paras Sehgal, Samatha Mathew, Ambily Sivadas, Arjun Ray, Jyoti Tanwar, Sushma Vishwakarma, Gyan Ranjan, K V Shamsudheen, Rahul C. Bhoyar, Abhishek Pateria, Elvin V. Leonard, Mukesh Kumar Lalwani, Archana Vats, Rajeev Reddy Pappuru, Mudit Tyagi, Saumya Jakati, Shantanu Sengupta, Binukumar BK, Subhabrata Chakrabarti, Inderjeet Kaur, Rajender K. Motiani, Vinod Scaria, Sridhar Sivasubbu
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. Protein kinase C beta (PRKCB) promotes vascular permeability, and its hyper‐activation has been linked to diabetic retinopathy. Here, the novel, evolutionarily conserved lncRNA VEAL2 is shown to inhibit PRKCB activity and junctional permeability in zebrafish and in human vascular endothelium. The evolutionarily conserved lncRNA VEAL2 enhances junctional integrity in developing zebrafish vasculature and in hyperglycemic vascular endothelium in humans.