Elevated glucose increases mesangial cell sensitivity to insulin-like growth factor I.
To determine the effects of glucose on insulin-like growth factor I (IGF-I)-induced mesangial cell (MC) proliferation, we have examined the relationships between IGF binding protein 2 (IGFBP-2) secretion and proliferation in murine MCs (MMCs). MMCs incubated in high glucose (HG, 25 mM) exhibited a 25-30% reduction in IGFBP-2 secretion compared with cells in normal glucose (NG, 5.6 mM). This loss was not due to cell surface binding; it correlated with a 3.1-fold decrease in IGFBP-2 mRNA. IGFBP-2 secretion was stimulated by IGF-I in NG but was unaltered in HG. Insulin treatment yielded similar results at 10-fold higher doses, indicating that this response is IGF-I receptor dependent. MMCs in HG displayed increased IGF-I-stimulated insulin receptor substrate-1/2 phosphorylation and activator protein-1 transcriptional activity compared with NG controls. Accordingly, although IGF-I was not proliferative in NG, it increased [3H]thymidine incorporation and cell number in HG to an extent proportional to the decrease in IGFBP-2. Thus hyperglycemia, as seen in diabetes, may increase MC IGF-I sensitivity by reducing IGFBP-2 expression, in turn increasing its proliferative and secretory responses and contributing to the development of diabetic glomerulosclerosis.
Horney
M J
MJ
Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Shirley
D W
DW
Kurtz
D T
DT
Rosenzweig
S A
SA
D000818:Animals; D002455:Cell Division; D002460:Cell Line / Q000187:drug effects; D003928:Diabetic Nephropathies / Q000209:etiology; D005920:Glomerular Mesangium / Q000166:cytology*; D005947:Glucose / Q000008:administration & dosage / Q000494:pharmacology*; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism
D018969:Insulin-Like Growth Factor Binding Proteins; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D005947:Glucose