Glucose-induced serum- and glucocorticoid-regulated kinase activation in oncofetal fibronectin expression.
Preferential expression of oncofetal extra domain-B fibronectin (EDB(+) FN), a proposed angiogenic marker, has been shown in proliferative diabetic retinopathy. High levels of glucose also increase EDB(+) FN expression in endothelial cells (ECs) via transforming growth factor-beta1 (TGF-beta1) and endothelin-1 (ET-1). The present study was aimed at elucidating the role of serum- and glucocorticoid-regulated kinase (SGK-1) in glucose-induced EDB(+) FN expression. Using human macro- and microvascular ECs, we show that high levels of glucose, TGF-beta1, and ET-1 increase the EDB(+) FN expression via SGK-1 alteration at the mRNA, protein, and activity levels. Inhibition of TGF-beta1 and ET-1 prevented glucose-induced SGK-1 activation and the EDB(+) FN expression. Furthermore, using siRNA-mediated SGK-1 gene silencing, we show that glucose-induced EDB(+) FN expression can be completely prevented. These findings provide first evidence of glucose-induced SGK-1 activation in altered EDB(+) FN expression and provide novel avenues for therapeutic modalities.
Khan
Zia A
ZA
Department of Pathology, University of Western Ontario, London, Ont., Canada.
Barbin
Yousef P
YP
Farhangkhoee
Hana
H
Beier
Norbert
N
Scholz
Wolfgang
W
Chakrabarti
Subrata
S
D015153:Blotting, Western; D002478:Cells, Cultured; D003930:Diabetic Retinopathy; D019332:Endothelin-1 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology*; D004789:Enzyme Activation; D005353:Fibronectins / Q000096:biosynthesis* / Q000737:chemistry / Q000378:metabolism*; D020868:Gene Silencing; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D017874:Immediate-Early Proteins; D015151:Immunoblotting; D008833:Microcirculation; D008856:Microscopy, Fluorescence; D009687:Nuclear Proteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D014471:Umbilical Veins / Q000166:cytology; D000099184:Serum-Glucocorticoid Regulated Kinases
D019332:Endothelin-1; D005353:Fibronectins; D005947:Glucose; D017874:Immediate-Early Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000099184:Serum-Glucocorticoid Regulated Kinases; C508960:TGFB1 protein, human; C121542:oncofetal fibronectin