title: Potential new medical therapies for diabetic retinopathy: protein kinase C inhibitors.
abstract: OBJECTIVE
  To review the evidence supporting a role for the beta (beta) isoform of protein kinase C (PKC) in the pathogenesis of diabetic retinopathy and the possible therapeutic benefit of inhibiting this enzyme.
  
  
  METHODS
  Brief literature review of research suggesting the potential use for systemic inhibitors of the beta isoform of PKC as a medical therapy to prevent the progression of diabetic retinopathy. Brief consideration is given to previous, primarily clinical, studies dealing with other therapies for this disease.
  
  
  RESULTS
  Kinases transfer the terminal, "high energy," phosphate group of ATP to a site on a target protein, thereby activating the protein, which may be an enzyme, cell membrane receptor, or ion transport channel. The PKC family is a group of such enzymes that require specific activator molecules, including diacylglycerol, whose intracellular concentration is substantially increased during the hyperglycemia of diabetes. Protein kinase Cbeta is present at high levels in the retina. Increased activation of this enzyme, perhaps by producing tissue hypoxia, leads to increased expression of vascular endothelial growth factor, a mitogen that increases proliferation of vascular endothelial cells leading to neovascularization and enhances breakdown of the blood-retinal barrier, perhaps resulting in macular edema.
  
  
  CONCLUSIONS
  By interfering with the above biochemical pathways, PKC inhibitors may retard or prevent the development and progression of diabetic retinopathy. Because members of the PKC family are found throughout the body, a generalized inhibitor is likely to be toxic. However, an inhibitor specific for PKCbeta may act effectively within the retina and have a favorable toxicity profile. Two phase III randomized controlled clinical trials of such an inhibitor are now in progress, attempting to evaluate the efficacy of this approach to preventing the progression, or inducing regression, of "nonclinically significant" diabetic macular edema and of severe nonproliferative diabetic retinopathy.
authors: The Kresge Eye Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA. rnfrank@med.wayne.edu
authors: Robert N
authors: RN
authors: Frank
mesh_terms: D017326:Clinical Trials, Phase III as Topic; 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*; D008301:Maleimides / Q000627:therapeutic use*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D007527:Isoenzymes; D008301:Maleimides; C099154:ruboxistaurin; D011493:Protein Kinase C; D064546:Protein Kinase C beta