title: Notch signaling protects retina from nuclear factor-κB- and poly-ADP-ribose-polymerase-mediated apoptosis under high-glucose stimulation.
abstract: Proliferative diabetic retinopathy, the primary cause of vision loss in adults, is one of serious microvascular complications caused by diabetes. Both poly-ADP-ribose-polymerase (PARP) and nuclear factor (NF)-κB signaling are involved in the injury process. Injury activates PARP, which in turn potentiates NF-κB activation and causes cell apoptosis. Like the NF-κB pathway, Notch1 signaling plays a key role in the regulation of cell proliferation, differentiation, and apoptosis. However, the connections between these signaling pathways are not well understood. In this study, we used both streptozotocin (STZ)-induced diabetic mice and human retinal vascular endothelial cells (HRVECs) cultured in high glucose to detect these relationships. We found that apoptosis was increased in both STZ-induced diabetic mice and high-glucose-treated HRVECs, which was due to increased activation of PARP, cleaved caspase3, and reduced expression of Notch1 and p-Akt. The results of Notch1 overexpression and knockdown indicated that Notch1 signaling participated in the interaction of PARP and p50, and inhibited PARP- and p50-mediated apoptosis directly. These phenomena could be blocked by pretreatment with the PI3K inhibitor wortmannin via reducing p-Akt levels. Thus, our study demonstrated that Notch1 signaling protects cells from PARP- and NF-κB-induced apoptosis under high glucose through the activation of Akt.
authors.affiliation: Department of Ophthalmology, the Second Hospital of Jilin University, Changchun, China.
authors.forename: Xiuhong
authors.initials: X
authors.lastname: Qin
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Haitao
authors.initials: H
authors.lastname: Xu
authors.forename: Yazhen
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D053148:Caspase 3; D005947:Glucose; D049452:Green Fluorescent Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D051057:Proto-Oncogene Proteins c-akt; D051881:Receptor, Notch1; D000077191:Wortmannin