Autocrine activation of the
IGF-I system in mesangial cells (MC) promotes glomerular
scarring in a model of
type 1 diabetes. Although
estrogens protect against progressive nondiabetic 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 nondiabetic db/+ littermates. We found increased
IGF-I receptor (IGFR) expression and activation, including activation of MAPK. Surprisingly,
estrogens, via an
estrogen receptor (ER)-independent mechanism(s), increased IGFR expression, IGFR and
insulin receptor substrate phosphorylation, and
extracellular signal-regulated kinase 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
PD98059 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. Although
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 antisclerotic 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.