title: Cellular signaling and potential new treatment targets in diabetic retinopathy.
abstract: Dysfunction and death of microvascular cells and imbalance between the production and the degradation of extracellular matrix (ECM) proteins are a characteristic feature of diabetic retinopathy (DR). Glucose-induced biochemical alterations in the vascular endothelial cells may activate a cascade of signaling pathways leading to increased production of ECM proteins and cellular dysfunction/death. Chronic diabetes leads to the activation of a number of signaling proteins including protein kinase C, protein kinase B, and mitogen-activated protein kinases. These signaling cascades are activated in response to hyperglycemia-induced oxidative stress, polyol pathway, and advanced glycation end product formation among others. The aberrant signaling pathways ultimately lead to activation of transcription factors such as nuclear factor-kappaB and activating protein-1. The activity of these transcription factors is also regulated by epigenetic mechanisms through transcriptional coactivator p300. These complex signaling pathways may be involved in glucose-induced alterations of endothelial cell phenotype leading to the production of increased ECM proteins and vasoactive effector molecules causing functional and structural changes in the microvasculature. Understanding of such mechanistic pathways will help to develop future adjuvant therapies for diabetic retinopathy.
authors.affiliation: Department of Pathology, University of Western Ontario, London, Ontario, Canada. zia.khan@schulich.uwo.ca
authors.forename: Zia A
authors.initials: ZA
authors.lastname: Khan
authors.forename: Subrata
authors.initials: S
authors.lastname: Chakrabarti
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000473:pathology; D002196:Capillaries / Q000473:pathology; D016923:Cell Death; D003930:Diabetic Retinopathy / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D019332:Endothelin-1 / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000502:physiology; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D006943:Hyperglycemia / Q000150:complications; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014661:Vasoconstriction / Q000502:physiology; D014664:Vasodilation / Q000502:physiology
chemical_list: D019332:Endothelin-1; D011493:Protein Kinase C; D005947:Glucose