title: 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.
abstract: 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.
authors.affiliation: Vascular Biology Institute, University of Miami School of Medicine, 1600 N.W. 10th Avenue, RMSB, Room 1043-R104, Miami, Florida 33136, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Karl
authors.forename: Mylene
authors.initials: M
authors.lastname: Potier
authors.forename: Ivonne H
authors.initials: IH
authors.lastname: Schulman
authors.forename: Ana
authors.initials: A
authors.lastname: Rivera
authors.forename: Haim
authors.initials: H
authors.lastname: Werner
authors.forename: Alessia
authors.initials: A
authors.lastname: Fornoni
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Elliot
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D015153:Blotting, Western; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000503:physiopathology*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism* / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005920:Glomerular Mesangium / Q000166:cytology / Q000503:physiopathology; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D017526:Receptor, IGF Type 1 / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D018969:Insulin-Like Growth Factor Binding Proteins; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1; D048049:Extracellular Signal-Regulated MAP Kinases