The potential role of PKC beta in diabetic retinopathy and macular edema.
Diabetic retinopathy is one of the most debilitating complications of diabetes mellitus. Despite major advances in understanding the pathogenesis of this disease and the efficacy of current therapies, diabetic retinopathy remains the leading cause of new-onset blindness among working-age people. The mainstay of current therapy, laser photocoagulation, is useful in preventing blindness and severe vision loss but is not often effective in restoring lost visual acuity. In addition, troublesome side effects and potentially serious complications may occur. Diabetic retinopathy is characterized by a progression of abnormalities. Nonproliferative retinopathy results from a series of biochemical and cellular changes that ultimately cause progressive retinal ischemia. The subsequent elaboration of growth factors in response to ischemia leads to the development of proliferative retinopathy, which is characterized by aberrant neovacularization of the retina-potentially leading to severe, irreversible visual loss. Increased retinal vascular leakage may also occur at any stage in this process, resulting in macular edema and possible progressive visual impairment. Although numerous biochemical factors are thought to play a role in the development of retinopathy, activation of protein kinase C (PKC), specifically the beta isoform of PKC (PKC beta), is implicated for both the early and late-stage manifestations of retinopathy. Studies suggest that orally administered LY333531, a beta-isoform specific PKC inhibitor, may be effective in ameliorating retinopathy progression, proliferation, and retinal vascular leakage. The status of ongoing clinical trials aimed at addressing the efficacy of PKC beta with regard to diabetes-induced retinal complications and perspectives on the role of PKC beta are presented.
Aiello
Lloyd Paul
LP
Harvard Medical School and Joslin Diabetes Center, Boston, Massachussetts, USA.
D000818:Animals; D003930:Diabetic Retinopathy / Q000188:drug therapy / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology*; D008269:Macular Edema / Q000188:drug therapy / Q000201:enzymology*; D008301:Maleimides / Q000627:therapeutic use; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D064546:Protein Kinase C beta
D004791:Enzyme Inhibitors; D007211:Indoles; D007527:Isoenzymes; D008301:Maleimides; C099154:ruboxistaurin; D011493:Protein Kinase C; D064546:Protein Kinase C beta