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.

Schlüsselwörter

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

Key words

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

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