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B and AP-1 in increased
fibronectin synthesis in target organs of diabetic
complications
Department of Pathology, University of Western Ontario, London, Ontario N6A 5C1, Canada
Increased
extracellular matrix protein production leading to structural
abnormalities is a characteristic feature of chronic diabetic
complications. We previously showed that high glucose in endothelial
cell culture leads to the upregulation of basement membrane protein
fibronectin (FN) via an endothelin (ET)-dependent pathway involving
activation of NF-
B and activating protein-1 (AP-1). To delineate the
mechanisms of basement membrane thickening, we used an animal model of
chronic diabetes and evaluated ET-dependent activation of NF-B and
AP-1 and subsequent upregulation of FN in three target organs of
chronic diabetic complications. After 3 mo of diabetes, retina, renal
cortex, and myocardium demonstrated increased FN mRNA and increased
ET-1 mRNA expression. Increased FN expression was shown to be dependent
on ET receptor-mediated signaling, as the increase was prevented by the
dual ET receptor antagonist bosentan. NF-B activation was most
pronounced in the retina, followed by kidney and heart. AP-1 activation
was also most pronounced in the retina but was similar in both kidney
and heart. Bosentan treatment prevented NF-B activation in the
retina and heart and AP-1 activation in the retina and kidney. These data indicate that, although ETs are important in increased FN production due to diabetes, the mechanisms with respect to
transcription factor activation may vary depending on the
microenvironment of the organ.
activating protein-1; nuclear factor-B; endothelin; retina; kidney; heart; diabetes
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