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Glucose-induced Akt1 activation mediates fibronectin synthesis in endothelial cells.
- Source :
-
Diabetologia [Diabetologia] 2005 Nov; Vol. 48 (11), pp. 2428-36. Date of Electronic Publication: 2005 Sep 29. - Publication Year :
- 2005
-
Abstract
- Aims/hypothesis: Increased expression and decreased degradation of extracellular matrix (ECM) proteins are key features of chronic diabetic complications. Fibronectin, a predominant ECM protein, has been shown to be overexpressed in all target organs of diabetic complications and in endothelial cells cultured in high levels of glucose. The present study was designed to elucidate the role of protein kinase B (Akt/PKB) in glucose-induced fibronectin mRNA expression and protein production in vascular endothelial cells.<br />Methods: Human umbilical vein endothelial cells were cultured in the presence of high glucose to study Akt/PKB activation. The upstream and downstream mediators in the Akt/PKB pathway were also investigated using dominant negative transfections and specific inhibitors of signalling pathways. Cells were subjected to real time RT-PCR, western blotting, and confocal microscopy to assess Akt1/PKBalpha activation and fibronectin mRNA expression and protein production. To detect transcription factor activation, electrophoretic mobility shift assay was carried out.<br />Results: Our data demonstrate that fibronectin mRNA expression and protein production that are induced by high glucose are mediated via activation of Akt/PKB, which is modulated by mitogen-activated protein kinase, phosphatidylinositol 3-kinase, and protein kinase C. Glucose-induced fibronectin mRNA expression and protein production are also mediated by Akt1/PKBalpha-dependent activation of the transcription factors nuclear factor-kappaB and activating protein-1.<br />Conclusions/interpretation: Our study provides insight into the mechanical basis of glucose-induced increases in fibronectin mRNA expression and protein production. High levels of glucose may increase fibronectin mRNA expression and protein production by activating Akt/PKB.
- Subjects :
- Cell Survival drug effects
Cells, Cultured
Endothelial Cells drug effects
Endothelial Cells metabolism
Endothelium, Vascular cytology
Endothelium, Vascular drug effects
Enzyme Activation drug effects
Enzyme Inhibitors pharmacology
Fibronectins drug effects
Fibronectins genetics
Glucose pharmacology
Humans
NF-kappa B drug effects
NF-kappa B metabolism
Proto-Oncogene Proteins c-akt antagonists & inhibitors
Proto-Oncogene Proteins c-akt drug effects
Proto-Oncogene Proteins c-akt genetics
RNA, Messenger drug effects
RNA, Messenger metabolism
Transcription Factor AP-1 drug effects
Transcription Factor AP-1 metabolism
Up-Regulation
Endothelium, Vascular metabolism
Fibronectins biosynthesis
Glucose metabolism
Proto-Oncogene Proteins c-akt metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0012-186X
- Volume :
- 48
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Diabetologia
- Publication Type :
- Academic Journal
- Accession number :
- 16193290
- Full Text :
- https://doi.org/10.1007/s00125-005-1939-4