Insight review articles
Activation of protein kinase C
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| Activation of protein kinase C
The PKC family comprises at least eleven isoforms, nine of which are activated by the lipid second messenger DAG. Intracellular hypergly- caemia increases the amount of DAG in cultured microvascular cells and in the retina and renal glomeruli of diabetic animals. It seems to achieve this primarily by increasing de novo DAG synthesis from the glycolytic intermediate dihydroxyacetone phosphate, through reduc- tion of the latter to glycerol-3-phosphate and stepwise acylation 54 . Increased de novo synthesis of DAG activates PKC both in cultured vascular cells 55 and in retina and glomeruli of diabetic animals 54 . The b- and d-isoforms of PKC are activated primarily, but increases in other isoforms have also been found, such as PKC- aand -;isoforms in the retina 54 and PKC- a and -b in glomeruli 56 of diabetic rats. Hyperglycaemia may also activate PKC isoforms indirectly through both ligation of AGE receptors 57 and increased activity of the polyol- pathway 58 , presumably by increasing reactive oxygen species. In early experimental diabetes, activation of PKC- b isoforms has been shown to mediate retinal and renal blood flow abnormalities 59 , perhaps by depressing nitric oxide production and/or increasing endothelin-1 activity (Fig. 3). Abnormal activation of PKC has been insight review articles NATURE | VOL 414 | 13 DECEMBER 2001 | www.nature.com 815 Glucose Glucose Integrins Matrix Intracellular transducers Proteins Intracellular protein glycation AGE precursors ROS NF- κ B Endothelial cell Macrophage/ mesangial cell mRNA RNA DNA Transcription factors Transcription AGE plasma proteins AGE receptor Growth factors and cytokines AGE receptor Figure 2 Mechanisms by which intracellular production of advanced glycation end-product (AGE) precursors damages vascular cells. Covalent modification of intracellular proteins by dicarbonyl AGE precursors alters several cellular functions. Modification of extracellular matrix proteins causes abnormal interactions with other matrix proteins and with integrins. Modification of plasma proteins by AGE precursors creates ligands that bind to AGE receptors, inducing changes in gene expression in endothelial cells, mesangial cells and macrophages. tải về 382.68 Kb. Chia sẻ với bạn bè của bạn:
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