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Submitted on August 24, 2004
Accepted on November 8, 2004
Vascular Biology Institute, Department of Medicine, University of Miami School of Medicine, Miami, Fl Department of Clinical Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv Israel
* To whom correspondence should be addressed. E-mail: selliot{at}med.miami.edu.
Autocrine activation of the insulin-like growth factor I (IGF-I) system in mesangial cells (MC) promotes glomerular scarring in a model of type 1 diabetes. While estrogens protect against progressive non-diabetic glomerulosclerosis (GS), women with diabetes seem to loose the estrogen-mediated protection against cardiovascular disease. However, little is known about the local IGF-I system and its interactions with estrogens in the pathogenesis of type 2 diabetic GS. Therefore, we examined db/db B6 (db/db) mice, a model of type 2 diabetes and diabetic GS. The IGF-I system was activated in the glomeruli and MC of female diabetic db/db mice, but not in non-diabetic db/+ littermates. We found increased IGF-I receptor (IGFR) expression and activation including activation of MAPK. Surprisingly, estrogens via estrogen receptor (ER)-independent mechanism(s) increased IGFR expression, IGFR and IRS phosphorylation and ERK activation in db/db MC. In contrast, ER expression was decreased in MC and glomeruli of db/db mice. Treatment with a neutralizing antibody to IGF-I or the MAPK inhibitor PD increased ER expression and transcriptional activity. This suggests that the local prosclerotic IGF-I system is activated in type 2 diabetes and diminishes ER-mediated protection against GS. While estrogens may stimulate protective ER signaling, they also activate the IGF-I system via ER-independent mechanisms in db/db MC. The later estrogen effects appear to outweigh the anti-sclerotic effects of ER activation. This may, in part, account for loss of estrogen protection against the progression of diabetic GS in women with type 2 diabetes.
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