title: Adrenergic and serotonin receptors affect retinal superoxide generation in diabetic mice: relationship to capillary degeneration and permeability.
abstract: Reactive oxygen species play an important role in the pathogenesis of diabetic retinopathy. We studied the role of adrenergic and serotonin receptors in the generation of superoxide by retina and 661W retinal cells in high glucose and of the α1-adrenergic receptor (AR) on vascular lesions of the retinopathy in experimentally diabetic C57Bl/6J mice (and controls) after 2 and 8 months. Compared with 5 mM glucose, incubating cells or retinal explants in 30 mM glucose induced superoxide generation. This response was reduced or ablated by pharmacologic inhibition of the α1-AR (a Gq-coupled receptor) or Gs-coupled serotonin (5-HT2, 5-HT4, 5-HT6, and 5-HT7) receptors or by activation of the Gi-coupled α2-AR. In elevated glucose, the α1-AR produced superoxide via phospholipase C, inositol triphosphate-induced Ca(2+) release, and NADPH oxidase, and pharmacologic inhibition of these reactions prevented the superoxide increase. Generation of retinal superoxide, expression of proinflammatory proteins, and degeneration of retinal capillaries in diabetes all were significantly inhibited with daily doxazosin or apocynin (inhibitors of α1-AR and NADPH oxidase, respectively), but increased vascular permeability was not significantly affected. Adrenergic receptors, and perhaps other GPCRs, represent novel targets for inhibiting the development of important features of diabetic retinopathy.
authors: *Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA; Department of Ophthalmology and Visual Sciences, The University of Michigan, Ann Arbor, Michigan, USA; Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA; and Veterans Administration Medical Center Research Service 151, Cleveland, Ohio, USA.
authors: Yunpeng
authors: Y
authors: Du
authors: *Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA; Department of Ophthalmology and Visual Sciences, The University of Michigan, Ann Arbor, Michigan, USA; Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA; and Veterans Administration Medical Center Research Service 151, Cleveland, Ohio, USA.
authors: Megan
authors: M
authors: Cramer
authors: *Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA; Department of Ophthalmology and Visual Sciences, The University of Michigan, Ann Arbor, Michigan, USA; Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA; and Veterans Administration Medical Center Research Service 151, Cleveland, Ohio, USA.
authors: Chieh Allen
authors: CA
authors: Lee
authors: *Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA; Department of Ophthalmology and Visual Sciences, The University of Michigan, Ann Arbor, Michigan, USA; Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA; and Veterans Administration Medical Center Research Service 151, Cleveland, Ohio, USA.
authors: Jie
authors: J
authors: Tang
authors: *Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA; Department of Ophthalmology and Visual Sciences, The University of Michigan, Ann Arbor, Michigan, USA; Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA; and Veterans Administration Medical Center Research Service 151, Cleveland, Ohio, USA.
authors: Arivalagan
authors: A
authors: Muthusamy
authors: *Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA; Department of Ophthalmology and Visual Sciences, The University of Michigan, Ann Arbor, Michigan, USA; Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA; and Veterans Administration Medical Center Research Service 151, Cleveland, Ohio, USA.
authors: David A
authors: DA
authors: Antonetti
authors: *Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA; Department of Ophthalmology and Visual Sciences, The University of Michigan, Ann Arbor, Michigan, USA; Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA; and Veterans Administration Medical Center Research Service 151, Cleveland, Ohio, USA.
authors: Hui
authors: H
authors: Jin
authors: *Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA; Department of Ophthalmology and Visual Sciences, The University of Michigan, Ann Arbor, Michigan, USA; Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA; and Veterans Administration Medical Center Research Service 151, Cleveland, Ohio, USA.
authors: Krzysztof
authors: K
authors: Palczewski
authors: *Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA; Department of Ophthalmology and Visual Sciences, The University of Michigan, Ann Arbor, Michigan, USA; Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA; and Veterans Administration Medical Center Research Service 151, Cleveland, Ohio, USA tsk@case.edu.
authors: Timothy S
authors: TS
authors: Kern
mesh_terms: D000818:Animals; D002196:Capillaries / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000503:physiopathology; D003930:Diabetic Retinopathy / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011941:Receptors, Adrenergic / Q000235:genetics / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000166:cytology / Q000378:metabolism; D012162:Retinal Degeneration / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013481:Superoxides / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D011941:Receptors, Adrenergic; D011985:Receptors, Serotonin; D013481:Superoxides; D000242:Cyclic AMP
keywords: GPCRs; NADPH oxidase; diabetic retinopathy; inflammation