Autocrine Activation of the Local Insulin-Like Growth Factor I System Is Up-Regulated by Estrogen Receptor (ER)-Independent Estrogen Actions and Accounts for Decreased ER Expression in Type 2 Diabetic Mesangial Cells
Endocrinology. 2005-02-01; 146(2): 889-900
DOI: 10.1210/en.2004-1121
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1. Endocrinology. 2005 Feb;146(2):889-900. doi: 10.1210/en.2004-1121. Epub 2004
Nov 18.
Autocrine activation of the local insulin-like growth factor I system is
up-regulated by estrogen receptor (ER)-independent estrogen actions and accounts
for decreased ER expression in type 2 diabetic mesangial cells.
Karl M(1), Potier M, Schulman IH, Rivera A, Werner H, Fornoni A, Elliot SJ.
Author information:
(1)Vascular Biology Institute, University of Miami School of Medicine, 1600 N.W.
10th Avenue, RMSB, Room 1043-R104, Miami, Florida 33136, USA.
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.
DOI: 10.1210/en.2004-1121
PMID: 15550505 [Indexed for MEDLINE]