Die Bedeutung der Proteinkinase C in der Pathophysiologie der diabetischen Retinopathie

Zusammenfassung

Die Kontrolle der Hyperglykämie bei Diabetes mellitus ist eine wesentliche Voraussetzung, um die Entwicklung und Progression der diabetischen Retinopathie zu verhindern. Ein wichtiger Pathomechanismus in der Entwicklung von diabetischen Folgeerkrankungen ist die durch erhöhte Glukose induzierte Aktivierung der Proteinkinase C (PKC) infolge eines erhöhten Diazylglyzerolspiegels (DAG). Aus der Aktivierung der PKC resultieren vaskuläre Dysfunktionen in Form gesteigerter Gefäßpermeabilität, erhöhter Gefäßkontraktilität, vermehrter Produktion extrazellulärer Matrix und gesteigerter Zellproliferation. Die Familie der PKC-Isoenzyme spielt eine fundamentale Rolle bei der zellulären Signaltransduktion durch Phosphorylierung und Modifikation von Enzymen, Rezeptoren, Transkriptionsfaktoren und anderen Kinasen. Die PKC-Aktivierung beeinflusst auch die Gentranskription und den Ionentransport. Verschiedene PKC-Isoenzyme fungieren als Mediatoren aber auch als Inhibitoren der Insulinwirkung. Die durch Hyperglykämie induzierte DAG-Ausschüttung scheint in retinalen vaskulären Endothelzellen vornehmlich PKC-β zu aktivieren. Die Entwicklung von isoenzymselektiven PKC-β-Inhibitoren ermöglicht neue medikamentöse Therapieansätze zur Behandlung der diabetischen Retinopathie. Derzeit wird in klinischen Studien untersucht, ob die Therapie mit einem spezifischen PKC-β-Inhibitor das Fortschreiten der diabetischen Retinopathie und des diabetischen Makulaödems verhindern kann.

Abstract

Hyperglycemic control in diabetes mellitus is a major key to prevent the development and progression of diabetic retinopathy. One important pathomechanism in the development of diabetic complications is the activation of protein kinase C (PKC) induced by high glucose due to an increased diacylglycerol (DAG) level. Resulting vascular dysfunctions are increased vascular permeability and contractility, increased production of extracellular matrix and cell proliferation. The PKC isoenzyme family plays a fundamental role in the cellular signal transduction via phosphorylation and modification of enzymes, receptors, transcription factors and kinases. The PKC activation influences the gene transcription and ion transport. Different PKC isoenzymes function as mediators but also as inhibitors of the insulin effects. The hyperglycemia induced DAG production seems to predominantly activate PKC-β in retinal vascular endothelial cells. The development of selective PKC-β inhibitors enables new pharmacological therapeutical approaches for treatment of diabetic retinopathy. Ongoing clinical studies investigate if the treatment with specific PKC-β inhibitors can prevent the progression of diabetic retinopathy and diabetic macular edema.

Proteinkinase C (PKC) - Diazylglyzerol (DAG) - PKC-Isoenzyme - LY333531 - Vitamin E - diabetische Retinopathie

Protein kinase C (PKC) - Diacylglycerol (DAG) - PKC isoenzymes - LY333531 - vitamin E - diabetic retinopathy

Literatur

• 1 Aiello L P, Bursell S E, Clermont A. et al . Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective beta-isoform-selective inhibitor.  Diabetes. 1997;  46 1473-1480
• 2 Aiello L P, Gardner T W, King G L. et al . Diabetic retinopathy (technical review).  Diabetes Care. 1998;  21 143-156
• 3 Aiello L P, Robinson G S, Lin Y W. et al . Identification in multiple genes in bovine retinal pericytes altered by exposure to elevated levels of glucose by using mRNA differential display.  Proc Natl Acad Sci USA. 1994;  91 6231-6235
• 4 Andrea J E, Walsh M P. Protein kinase C of smooth muscle.  Hypertension. 1992;  20 585-595
• 5 Avignon A, Yamada K, Zhou X. et al . Chronic activation of protein kinase C in soleus muscles and other tissues of insulin-resistant type II diabetic Goto-Kakizaki (GK), obese/aged, and obese Zucker rats.  Diabetes. 1996;  45 1396-1404
• 6 Ayo S H, Radnik R A, Garoni J. et al . High glucose causes an increase in extracellular matrix proteins in cultured mesangial cells.  Am J Pathol. 1990;  138 1339-1348
• 7 Ayo S H, Radnik R A, Glass W F. et al . Increased extracellular matrix synthesis and mRNA in mesangial cells grown in high glucose medium.  Am J Physiol. 1991;  260 185-191
• 8 Bahr M, Spenlieken M, Bock M. et al . Acute and chronic effects of troglitazone on isolated rat ventricular cardiomyocytes.  Diabetologica. 1996;  39 766-774
• 9 Bandyopadhyay G, Standaert M, Galloway L. et al . Evidence for involvement of protein kinase C (PKC)- ξ and noninvolvement of diacylglycerol-sensitive PKCs in insulin-stimulated glucose transport in L6 myotubes.  Endocrinology. 1999;  138 4721-4731
• 10 Berti L, Mosthaf L, Kroder G. et al . Glucose-induced translocation of protein kinase C isoforms in rat-1 fibroblasts is paralleled by inhibition of the insulin receptor tyrosine kinase.  J Biol Chem. 1994;  269 3381-3386
• 11 Blackmore P F, Strickland W G, Exton J H. Phosphorylation of glycogen synthase by protein kinase C.  Biochem J. 1986;  237 235-242
• 12 Boggs K P, Farese R V, Buse M G. Insulin administration in vivo increases 1,2-diacylglycerol in rat skeletal muscle.  Endocrinology. 1991;  128 636-638
• 13 Bollag G B, Roth R A, Beaudoin J. et al . PKC directly phosphorylates the insulin receptor in vitro and reduces its protein-tyrosine kinase activity.  Proc Natl Acad Sci USA. 1986;  83 5822-5824
• 14 Bollineni J S, Reddi A S. Transforming growth factor TGF-β₁ enhances glomerular collagen synthesis in diabetic rats.  Diabetes. 1993;  42 1673-1677
• 15 Boneh A. Possible role of protein kinase C in the pathogenesis of inborn errors of metabolism.  J Cell Biochem. 1995;  59 27-32
• 16 Bursell S E, Clemont A C, Aiello L P. et al . High-dose vitamin E supplementation normalises retinal blood flow and creatinine clearance in patients with type-1 diabetes.  Diabetes Care. 1999;  22 1245-1251
• 17 Busch A K, Castan I, Degerman E. et al . Protein kinase C mediates hyperglycaemia-induced insulin resistance through serine phosphorylation of IRS-1.  Diabetologica. 1998;  41 10
• 18 Cagliero E, Roth T, Roy S. et al . Expression of genes related the extracellular matrix in human endothelial cells.  Biol Chem. 1991;  266 14244-14250
• 19 Cagliero E, Roth T, Roy S. et al . Characteristics and mechanisms of high glucose-induced overexpression of basement membrane components in cultured endothelial cells.  Diabetes. 1991;  40 102-110
• 20 Carlin S, Yang K XF, Donnelly R, Black J L. Protein kinase C isoforms in human airway smooth muscle cells - A role for PKC-ξ in proliferation.  Am J Physiol. 1999;  276 506-512
• 21 Castagna M, Takai Y, Kaibuchi K. et al . Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters.  J Biol Chem. 1982;  257 7847-7851
• 22 Caukai M, Molchy-Rosen D. Pharmacologic modulation of protein kinase isoforms: the role of RACKs and subcellular localization.  Pharmacol Res. 1999;  39 253-259
• 23 Chakravarthy U, Hayes R, Stitt A. et al . Constitutive nitric oxide synthase expression in retinal vascular endothelial cells is suppressed by high glucose and advanced glycation end-products.  Diabetes. 1998;  47 945-952
• 24 Chiu R, Boile W J, Meek J. et al . The c-Fos protein interacts with C-Jun/AP-1 responsive genes.  Cell. 1988;  54 541-552
• 25 Considine R V, Nyce M R, Allen L E. et al . Protein kinase C is increased in the liver of humans and rats with non-insulin-dependent diabetes mellitus: an alteration not due to hyperglycaemia.  J Clin Invest. 1995;  95 2938-2944
• 26 Cortright R N, Muoio D M, Dohm G L. Skeletal muscle lipid metabolism: a frontier for new insights into fuel homeostasis.  Nut Biochem. 1997;  8 228-245
• 27 Craven P A, Davidson C M, DeRubertis F R. Increase in diacylglycerol mass in isolated glomeruli by glucose from de novo synthesis of glycerolipids.  Diabetes. 1990;  39 667-674
• 28 Cunha-Vaz J G. Vitreous fluorometry. In: Osborne MN, Ghader (eds) Progress in Retinal Research. Oxford; Pergamon Press 1985: 90-114
• 29 Danis R P, Bingaman D P, Jirousek M. et al . Inhibition of intraocular neovascularisation caused by retinal ischaemia in pigs by PKC-β inhibition with LY333531.  Invest Ophthalmol Vis Sci. 1998;  39 171-179
• 30 Diabetic Retinopathy Study Research Group . Report 8: Photocoagulation treatment of proliferative diabetic retinopathy: Clinical applications of Diabetic Retinopathy Study (DRS) findings.  Ophthalmology. 1981;  88 583-600
• 31 Donnelly R, Reed M J, Azhar S, Reaven G M. Expression of the major isoenzyme of protein kinase C in skeletal muscle, PKC-Θ, varies with muscle type and in response to fructose-induced insulin resistence.  Endocrinology. 1994;  135 2369-2374
• 32 Early Treatment Diabetic Retinopathy Study Research Group . Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report Number One.  Arch Ophthalmolol. 1985;  103 1796-1806
• 33 Edwards A S, Faux M C, Scott J D. et al . Carboxyl-terminal phosphorylation regulates the function and subcellular localization of protein kinase C β_II.  J Biol Chem. 1999;  274 6461-6468
• 34 Fabbro D, Ruetz S, Bodis S. et al . KC412 - a protein kinase inhibitor with a broad therapeutic potential.  Anti-Cancer Drug Design. 2000;  15 17-28
• 35 Fumo P, Kuncio G S, Ziyadeh F N. PKC and high glucose stimulate collagen α₁ transcriptional activity in a reporter mesangial cell line.  Am J Physiol. 1994;  267 632-638
• 36 Gabriele A, King G L. Proteinkinase C inhibitors in the treatment and prevention of diabetic complications.  Curr Opin Endocrinol Diabet. 2001;  8 197-204
• 37 Geschwendt M. Protein kinase C delta.  Eur J Biochem. 1999;  259 555-564
• 38 Goekjian P E, Jirousek M. Protein kinase C in the treatment of disease: signal transduction pathways, inhibitors, and agents in development.  Curr Med Chem. 1999;  6 877-903
• 39 Gregersen S, Thomsen J, Hermensen K. Endothelin-1 potentiated insulin secretion: involvement of protein kinase C and the ET_A receptor subtype.  Metabolism. 2000;  49 264-269
• 40 Griffin M E, Marcucci M J, Cline G W. et al . Free fatty acid-induced insulin resistance is associated with activation of protein kinase C-Θ and alterations in the insulin signalling cascade.  Diabetes. 1999;  48 1270-1274
• 41 Hanks S K, Quinn A M, Hunter T. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains.  Science. 1995;  241 42-52
• 42 Hayashi A, Seki N, Hattori A. et al . PKCnu, a new member of the protein kinase C family, composes a fourth subfamily with PKCmu.  Biochem Biophys Acta. 1999;  1450 99-106
• 43 Huang Q, Yuan Y. Interaction of PKC and NOS in signal transduction of microvascular hyperpermeability.  Am J Physiol. 1997;  273 2442-2451
• 44 Hunter T. Signaling - 2000 and beyond.  Cell. 2000;  100 113-127
• 45 Idris I, Gray S, Donnelly R. Protein kinase C aktivation: isozyme-specific effects on metabolism and cardiovascular complications in diabetes.  Diabetologica. 2001;  44 659-673
• 46 Inoguchi T, Battan R, Handler E. et al . Preferential elevation of protein kinase C isoform in β_ΙΙ and diacylglycerol levels in aorta and heart of diabetic rats: differential reversibility to glycemic control by islet cell transplantation.  Proc Natl Acad Sci USA. 1992;  89 11056-11063
• 47 Inoue M, Kishimoto A, Takai Y, Nishizuka Y. Studies on a cyclic nucleotide-independent protein kinase and its proenzyme in mammalian tissues. II. Proenzyme and its activation by calcium-dependent protease from rat brain.  J Biol Chem. 1977;  252 7610-7616
• 48 Ishii H, Jirousek M R, Koya D. et al . Amelioration of vascular dysfunctions in diabetic rats by an oral PKC-β inhibitor.  Science. 1996;  272 728-731
• 49 Itani S I, Zhou Q, Pories W J. et al . Involvement of protein kinase C in human skeletal muscle insulin resistance and obesity.  Diabetes. 2000;  49 1353-1358
• 50 Jamora C, Yamanouye N, van Lint J. et al . Gβγ-mediated regulation of Golgi organization is through the direct activation of protein kinase D.  Cell. 1999;  98 59-68
• 51 Johnson J E, Giorgione J, Newton A C. The C1 and C2 domains of protein kinase C are independent membrane targeting modules, with specifity for phosphatidylserine conferred by the C1 domain.  Biochemistry. 2000;  39 11360-11369
• 52 Kishimoto A, Takai Y, Mori T. et al . Activation of calcium and phospholipid-dependent protein kinase by diacylglycerol, its possible relation to phosphatidylinositol turnover.  J Biol Chem. 1980;  255 2273-2276
• 53 Konishi H, Tanaka M, Takemura Y. et al . Activation of protein kinase C by tyrosine phosphorylation in response to H₂O₂.  Proc Natl Acad Sci USA. 1997;  94 11233-11237
• 54 Kowluru R A, Jrousek M R, Stramm L. et al . Abnormalities of retinal metabolism in diabetes or experimental galactosemia: V. Relationship between protein kinase C and ATPase.  Diabetes. 1998;  47 464-469
• 55 Koya D, King G L. Protein kinase C activation and the development of diabetic complications.  Diabetes. 1998;  47 859-866
• 56 Koya D, Lee I K, Ishii H. et al . Prevention of glomerular dysfunction in diabetic rats by treatment with d-alpha-tocopherol.  J Am Soc Nephrol. 1997;  8 426-435
• 57 Kreuzer J, Denger S, Schmidts A. et al . Fibrinogen promotes monocyte adhesion via a protein kinase C dependent mechanism.  J Mol Med. 1996;  74 161-165
• 58 Kunisaki M, Bursell S E, Clermont A C. et al . Vitamin E prevents diabetes-induced abnormal retinal blood flow via the diacylglycerol-protein kinase C pathway.  Am J Physiol. 1995;  269 239-246
• 59 Kunisaki M, Bursell S E, Umeda F. et al . Normalisation of diacylglycerol-protein kinase C activation by vitamin E in aorta of diabetic rats and cultured rat smooth muscle cells exposed to elevated glucose levels.  Diabetes. 1994;  43 1372-1377
• 60 Kunisaki M, Fumio U, Nawata H. et al . Vitamin E normalises diacylglycerol-protein kinase C activation induced by hyperglycaemia in rat vascular tissues.  Diabetes. 1996;  45 117-119
• 61 Li P-F, Maasch C, Haller H. et al . Requirement for protein kinase C in reactive oxygen species-induced apoptosis of vascular smooth muscle cells.  Circulation. 1999;  100 967-973
• 62 Liao D-F, Monia B, Dean N. et al . Protein kinase C-ζ mediates angiotensin II activation of ERK1/2 in vascular smooth muscle cells.  J Biol Chem. 1997;  272 6146-6150
• 63 Liu W S, Heckman C A. The sevenfold way of PKC regulation.  Cell Signal. 1998;  10 529-542
• 64 Lu X, Yang X-Y, Howard R L, Walsh J P. Fatty acids modulate protein kinase C activation in porcine vascular smooth muscle cells independently of their effect on de novo diacylglycerol synthesis.  Diabetologica. 2000;  43 1136-1144
• 65 Malhotra A, Reich D, Nakouzi A. et al . Experimental diabetes is associated with functional acitivation of protein kinase C epsilon and phosphorylation of troponin-I in the heart, which are prevented by angiotensin II receptor blockade.  Circ Res. 1997;  81 1027-1033
• 66 Mischak H, Goodnight J A, Kolch W. et al . Overexpression of protein kinase C ™ and Σ, in NIH 3T3 cells induces opposite effects of growth, morphology, anchorage dependence, and tumorgenicity.  J Biol Chem. 1993;  268 6090-6096
• 67 Molchy-Rosen D, Wu G, Hahn H. et al . Cardiotrophic effects of protein kinase C: analysis by in vivo modulation of PKC translocation.  Circ Res. 2000;  86 1173-1179
• 68 Mosthaf L, Busch A K, Juhl L F. et al . The insulin receptor is degraded by specific PKC isoforms.  Diabetologica. 1998;  41 10
• 69 Muller H K, Kellerer M, Ermel B. et al . Prevention by protein kinase C inhibitors of glucose-induced insulin-receptor tyrosine kinase resistance in rat fat cells.  Diabetes. 1991;  40 1440-1448
• 70 Murphy M, Godson C, Cannon S. et al . Suppression subtractive hybridization identifies high glucose levels as a stimulus for expression of connective tissue growth factor and other genes in human mesangial cells.  J Biol Chem. 1999;  274 5830-5834
• 71 Newton A C. Protein kinase C: structure, function and regulation; minireview.  J Biol Chem. 1995;  270 28495-28498
• 72 Nishizuka Y. Protein kinase C and lipid signaling for sustained cellular responses.  FASEB J. 1995;  9 484-496
• 73 Nishizuka Y. The molecular etherogeneity of protein kinase C and its implication for cellular regulation.  Nature. 1988;  334 661-665
• 74 Park J-Y, Takahara N, Gabriele A. et al . Induction of endothelin-1 expression by glucose: an effect of protein kinase C activation.  Diabetes. 2000;  49 1239-1248
• 75 Phillips D IW, Caddy S, Iiic V. et al . Intramuscular triglyceride and muscle insulin sensitivity: evidence for a relationship in non-diabetic subjects.  Metabolism. 1996;  45 947-950
• 76 Pillay T S, Xiao S, Olefsky I M. Glucose-induced phosphorylation on the insulin receptor.  J Clin Invest. 1996;  97 613-620
• 77 Quyyumi A A. Endothelial function in health and disease: new insights into the genesis of cardiovascular disease.  Am J Med. 1998;  105 32-39
• 78 Riser B L, Denichilo M, Cortes P. et al . Regulation of connective tissue growth factor activity in cultured rat mesangial cells and its expression in experimental diabetic glomerulosclerosis.  J Am Soc Nephrol. 2000;  11 25-38
• 79 Ron D, Kazanietz M B. New insights into the regulation of protein kinase C and novel phorbol ester receptors.  FASEB J. 1999;  13 1658-1676
• 80 Schmitz-Peiffer C, Browne C L, Oakes N D. et al . Alterations in the expression and cellular localisation of protein kinase C isozymes ε and Θ are associated with insulin resistance in skeletal muscle of the high-fat fed rat.  Diabetes. 1997;  46 169-178
• 81 Sharma K, Jin Y, Guo J. Neutralization of TGF-β by anti-TGF-β antibody attenuates kidney hypertrophy and enhanced extracellular matrix gene expression in STZ-induced diabetic mice.  Diabetes. 1996;  45 522-530
• 82 Shiba T, Inoguchi T, Sportsman J R. et al . Correlation of diacylglycerol and protein kinase C activity in rat retina to retinal circulation.  Am J Physiol. 1993;  265 783-793
• 83 Shmueli E, Alberti K GM, Record C O. Diacylglycerol/protein kinase C signalling: a mechanism for insulin resistance?.  J Intern Med. 1993;  234 397-400
• 84 Spiro M J, Crowley T J. Increased rat myocardial type VI collagen in diabetes mellitus and hypertension.  Diabetologica. 1993;  36 93-96
• 85 Standaert M L, Galloway L, Karnam P. et al . Protein kinase C-ξ as a down-stream effector of phosphatidylinositol 3-kinase during insulin stimulation in rat adipocytes.  J Biol Chem. 1997;  272 30075-30082
• 86 Standl E, Schnell O. A new look at the heart in diabetes mellitus: from ailing to failing.  Diabetologica. 2000;  43 1455-1469
• 87 Stasek J E, Patterson C, Garcia J GN. Protein kinase C phosphorylates caldesmon-77 and vimentin and enhances albumin permeability across cultured bovine pulmonary artery endothelial monolayers.  J Cell Physiol. 1992;  153 62-75
• 88 Storlein L H, Borkman M, Jenkins A B. et al . Diet and in vivo insulin action: of rats and man.  Diabetes Nutr Metab. 1991;  4 227-240
• 89 Takagi C, Bursell S E, Lin Y-W. et al . Regulation of retinal heamodynamics in diabetic rats by increased expression and action of endothelin-1.  Invest Ophthalmol Vis Sci. 1996;  37 2504-2518
• 90 Takai Y, Kishimoto A, Iwasa Y. et al . Calcium-dependent activation of a multifunctional protein kinase by membrane phospholipids.  J Biol Chem. 1979;  254 3692-3695
• 91 The Diabetes Control and Complications Trial Research Group . The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.  N Engl J Med. 1993;  329 977-986
• 92 UK Prospective Diabetes Study (UKPDS) Group . Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).  Lancet. 1998;  352 837-853
• 93 Way K J, Katai N, King G L. Protein kinase C and the development of diabetic vascular complications.  Diabet Med. 2001;  18 945-959
• 94 Williams B, Gallacher B, Patel H. et al . Glucose-induced protein kinase C activation regulates vascular permeability factor mRNA expression and peptide production by human vascular smooth muscle cells in vitro.  Diabetes. 1997;  46 1497-1503
• 95 Williams B, Schrier R W. Characterisation of glucose-induced in situ protein kinase C activity in cultured vascular smooth muscle cells.  Diabetes. 1992;  41 1464-1472
• 96 Williams B. Glucose-induced vascular smooth muscle dysfunction: the role of protein kinase C.  J Hyperten. 1995;  13 477-486
• 97 Williamson J R, Kilo C. Extracellular matrix changes in diabetes mellitus. In: Scarpelli DG, Migahi G (eds) Comparative pathobiology of major age-related disease. NY; Liss 1984: 269-288
• 98 Xia P, Aiello L P, Ishii H. et al . Characterisation of vascular endothelial growth factor's effect on the activation of protein kinase C, its isoforms, and endothelial cell growth.  J Clin Invest. 1996;  98 2018-2026
• 99 Xia P, Inoguchi T, Kern T S. et al . Characterization of the mechanism for the chronic activation of diacylglycerol-protein kinase C pathway in diabetes and hypergalactosemia.  Diabetes. 1994;  43 1122-1129
• 100 Yazaki T, Ahmad S, Chahlavi A. et al . Treatment of glioblastoma U-87 by systemic administration of an antisense protein kinase C-alpha phosphorothioate oligodeoxynucleotide.  Mol Pharmacol. 1996;  50 236-242
• 101 Yu W, Niwa T, Fukasawa T. et al . Synergism of protein kinase A, protein kinase C, and myosin light-chain kinase in the secretory cascade of the pancreatic beta cell.  Diabetes. 2000;  49 945-952
• 102 Ziyadeh F N, Sharma K, Ericksen M. et al . Stimulation of collagen gene expression and protein synthesis in murine mesangial cells by high glucose is mediated by autocrine activation of transforming growth factor-β.  J Clin Invest. 1994;  93 536-542