Oncofetal fibronectin in diabetic retinopathy.
OBJECTIVE
Imbalance between extracellular matrix protein synthesis and degradation is a key feature of diabetic retinopathy. Fibronectin, a predominant constituent of the extracellular matrix, has been shown to undergo alternative splicing to produce embryonic isoforms in various pathologic conditions, such as fibrotic diseases and tumorigenesis. Two such isoforms, oncofetal fibronectin variants that are characterized by the inclusion of the oncofetal domains A and B, were the focus of the present study.


METHODS
The expression of oncofetal fibronectin variants was determined in human vitreous samples obtained from patients undergoing vitrectomy for proliferative diabetic retinopathy and nondiabetes-associated ocular conditions such as macular hole. In addition, an animal model of chronic diabetes and cultured endothelial cells was used to elucidate the mechanistic basis for this aberrant expression of oncofetal fibronectin.


RESULTS
Expression of fibronectin containing the oncofetal domain B was upregulated in the vitreous of patients with diabetic retinopathy.


CONCLUSIONS
Use of a well-established animal model of chronic diabetic complications and cultured endothelial cells showed that diabetes-induced upregulation of oncofetal fibronectin is, in part, dependent on hyperglycemia-induced transforming growth factor-beta1 and endothelin-1. Furthermore, the data suggest that oncofetal fibronectin is involved in endothelial cell proliferation.
Khan
Zia A
ZA
Department of Pathology, University of Western Ontario, London, Ontario, Canada.
Cukiernik
Mark
M
Gonder
John R
JR
Chakrabarti
Subrata
S
D000368:Aged; D000818:Animals; D015153:Blotting, Western; D000077300:Bosentan; D002455:Cell Division; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000601:surgery; D003930:Diabetic Retinopathy / Q000378:metabolism* / Q000601:surgery; D019332:Endothelin-1 / Q000378:metabolism / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects; D005260:Female; D005353:Fibronectins / Q000378:metabolism*; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D051381:Rats; D017207:Rats, Sprague-Dawley; D012167:Retinal Perforations / Q000378:metabolism / Q000601:surgery; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation; D014821:Vitrectomy; D014822:Vitreous Body / Q000378:metabolism*
D019332:Endothelin-1; D005353:Fibronectins; D013449:Sulfonamides; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C121542:oncofetal fibronectin; D000077300:Bosentan