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B and AP-1 in mediating endothelin-dependent increased fibronectin synthesis in target organs of diabetic complications
1 Department of Pathology, University of Western Ontario, London, ON, Canada
* To whom correspondence should be addressed. E-mail: schakrab{at}uwo.ca.
Increased extracellular matrix protein production, leading to structural abnormalities, is a characteristic feature of chronic diabetic complications. We have previously shown 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 nuclear factor-kappa B (NF-
B) and activating protein-1 (AP-1). To delineate the mechanisms of basement membrane thickening, we have used an animal model of chronic diabetes. We have evaluated endothelin-dependent activation of NF-B and AP-1 and subsequent upregulation of fibronectin in three target organs of chronic diabetic complications. Following three months of diabetes, retina, renal cortex, and myocardium demonstrated increased fibronectin mRNA and increased ET-1 mRNA expression. Increased FN expression was shown to be dependent on endothelin (ET)-receptor-mediated signaling, as the increase was prevented by 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 the kidney and heart. Bosentan treatment prevented NF-B activation in the retina and the 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 upon the microenvironment of the organ.
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