PKCbetaII/HuR/VEGF: A new molecular cascade in retinal pericytes for the regulation of VEGF gene expression.
Vascular endothelial growth factor (VEGF)-induced new vessels formation is a key event in diabetic retinopathy, a severe progressive multistage pathology. Literature data indicate that protein kinase C (PKC) is involved in the control of VEGF expression, but, so far, no data are available on the molecular pathway underlying this process. Within this context, we suggest the existence of a new molecular cascade, operating in retinal bovine pericytes and involving PKCbetaII, the mRNA-stabilizing protein HuR, and VEGF. In particular we show that PKCbetaII activation is responsible, through the RNA-binding protein HuR, for the increase of VEGF protein content and its release in the medium. The specificity of the PKCbetaII involvement is confirmed by experiments performed with the LY379196 compound, a selective PKCbetaII inhibitor. Following acute high-glucose insult this pathway seems still functioning, suggesting that a brief exposure to glucose does not compromise this molecular cascade in pericytes. A better understanding on this new pathway could open novel opportunities for the development of innovative pharmacological therapies useful in pathologies where VEGF plays a key role such as in diabetic retinopathy.
Amadio
Marialaura
M
Department of Experimental and Applied Pharmacology, Via Taramelli 14, 27100 Pavia, Italy. amadio@unipv.it
Scapagnini
Giovanni
G
Lupo
Gabriella
G
Drago
Filippo
F
Govoni
Stefano
S
Pascale
Alessia
A
D000818:Animals; D000954:Antigens, Surface / Q000502:physiology*; D002417:Cattle; D002478:Cells, Cultured; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D005786:Gene Expression Regulation; D020286:Pericytes / Q000378:metabolism*; D011493:Protein Kinase C / Q000502:physiology*; D064546:Protein Kinase C beta; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000502:physiology*; D012160:Retina / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D042461:Vascular Endothelial Growth Factor A; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D013755:Tetradecanoylphorbol Acetate