ArticleThe Biochemical journal2012
Novel atypical PKC inhibitors prevent vascular endothelial growth factor-induced blood-retinal barrier dysfunction.
Article in The Biochemical journal, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 62 citations in OpenAlex.
- The Basic Requirement of Tight Junction Proteins in Blood-Brain Barrier Function and Their Role in Pathologies.International journal of molecular sciences · 2024Review
- Selenium Protects ARPE-19 and ACBRI 181 Cells against High Glucose-Induced Oxidative Stress.Molecules (Basel, Switzerland) · 2023Article
- New Insights on Dietary Polyphenols for the Management of Oxidative Stress and Neuroinflammation in Diabetic Retinopathy.Antioxidants (Basel, Switzerland) · 2023Review
- The role of protein kinase C in diabetic microvascular complications.Frontiers in endocrinology · 2022Review
- Molecular Mechanisms Underlying the Therapeutic Role of Vitamin E in Age-Related Macular Degeneration.Frontiers in neuroscience · 2022Review
- Dual Function of Par3 in Tumorigenesis.Frontiers in oncology · 2022Review
- Future Perspectives of Therapeutic, Diagnostic and Prognostic Aptamers in Eye Pathological Angiogenesis.Cells · 2021Review
- Current understanding of the molecular and cellular pathology of diabetic retinopathy.Nature reviews. Endocrinology · 2021Review
- Retinal Physiology and Circulation: Effect of Diabetes.Comprehensive Physiology · 2020Review
- Synthesis and structure-activity relationships of thieno[2,3-d]pyrimidines as atypical protein kinase C inhibitors to control retinal vascular permeability and cytokine-induced edema.Bioorganic & medicinal chemistry · 2020Article
- Electrotonic transmission in the retinal vasculature: inhibitory role of the diabetes/VEGF/aPKC pathway.Physiological reports · 2019Article
- Tight junction proteins at the blood-brain barrier: far more than claudin-5.Cellular and molecular life sciences : CMLS · 2019Article
- Inhibition of Atypical Protein Kinase C Reduces Inflammation-Induced Retinal Vascular Permeability.The American journal of pathology · 2018Article
- Atypical Protein Kinase C: Breaking Down Barriers in Ocular Disease?The American journal of pathology · 2018Article
- The EPAC-Rap1 pathway prevents and reverses cytokine-induced retinal vascular permeability.The Journal of biological chemistry · 2018Article
- Impact of Metabolic Syndrome on Neuroinflammation and the Blood-Brain Barrier.Frontiers in neuroscience · 2018Review
- Diabetic retinopathy: Breaking the barrier.Pathophysiology : the official journal of the International Society for Pathophysiology · 2017Review
- Vascular endothelial growth factor-AClinical science (London, England : 1979) · 2017Article
- Regulatory mechanisms, prophylaxis and treatment of vascular leakage following severe trauma and shock.Military Medical Research · 2017Review
- Compound 49b Regulates ZO-1 and Occludin Levels in Human Retinal Endothelial Cells and in Mouse Retinal Vasculature.Investigative ophthalmology & visual science · 2017Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
Pro-inflammatory cytokines and growth factors such as VEGF (vascular endothelial growth factor) contribute to the loss of the BRB (blood-retinal barrier) and subsequent macular oedema in various retinal pathologies. VEGF signalling requires PKCβ [conventional PKC (protein kinase C)] activity; however, PKCβ inhibition only partially prevents VEGF-induced endothelial permeability and does not affect pro-inflammatory cytokine-induced permeability, suggesting the involvement of alternative signalling pathways. In the present study, we provide evidence for the involvement of aPKC (atypical PKC) signalling in VEGF-induced endothelial permeability and identify a novel class of inhibitors of aPKC that prevent BRB breakdown in vivo. Genetic and pharmacological manipulations of aPKC isoforms were used to assess their contribution to endothelial permeability in culture. A chemical library was screened using an in vitro kinase assay to identify novel small-molecule inhibitors, and further medicinal chemistry was performed to delineate a novel pharmacophore. We demonstrate that aPKC isoforms are both sufficient and required for VEGF-induced endothelial permeability. Furthermore, these specific, potent, non-competitive, small-molecule inhibitors prevented VEGF-induced tight junction internalization and retinal endothelial permeability in response to VEGF in both primary culture and in rodent retina. The results of the present study suggest that aPKC inhibition with 2-amino-4-phenyl-thiophene derivatives may be developed to preserve the BRB in retinal diseases such as diabetic retinopathy or uveitis, and the BBB (blood-brain barrier) in the presence of brain tumours.
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Registered trials
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