title: Autocrine activation of the IGF-I signaling pathway in mesangial cells isolated from diabetic NOD mice.
abstract: Mesangial cells isolated from NOD mice after the onset of diabetes have undergone a stable phenotypic change. This phenotype is characterized by increased expression of IGF-I and downregulation of collagen degradation, which is associated with decreased MMP-2 activity. Here, we investigated the IGF-I signaling pathway in mesangial cells isolated from NOD mice before (nondiabetic NOD mice [ND-NOD]) and after (diabetic NOD mice [D-NOD]) the onset of diabetes. We found that the IGF-I signaling pathway in D-NOD cells was activated by autocrine IGF-I. They had phosphorylation of the IGF-I receptor beta-subunit, phosphorylation of insulin receptor substrate (IRS)-1, and association of the p85 subunit (phosphatidylinositol 3-kinase [PI3K]) with the IGF-I receptor and IRS-1 in D-NOD cells in the basal state. This was also associated with increased phosphorylation of ERK2 in D-NOD mesangial cells. Inhibiting autocrine IGF-I from binding to its receptor using an IGF-I-neutralizing antibody or inhibiting IGF-I signaling pathways using a specific PI3K inhibitor or a specific mitogen-activated protein kinase/extracellular response kinase kinase inhibitor decreased phosphorylated ERKs in D-NOD cells. Importantly, this was associated with increased MMP-2 activity. The addition of exogenous IGF-I to ND-NOD activated signal transduction. Therefore, we conclude that the IGF-I signaling pathway is intact in both D-NOD and ND-NOD cells. However, the phenotypic change in D-NOD cells is associated with constitutive activation of the IGF-I signaling pathways, which may participate in the development and progression of diabetic glomerulosclerosis.
authors.affiliation: Physiology Laboratory, University of Toulouse School of Medicine, Toulouse, France.
authors.forename: Ivan
authors.initials: I
authors.lastname: Tack
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Elliot
authors.forename: Mylene
authors.initials: M
authors.lastname: Potier
authors.forename: Ana
authors.initials: A
authors.lastname: Rivera
authors.forename: Gary E
authors.initials: GE
authors.lastname: Striker
authors.forename: Liliane J
authors.initials: LJ
authors.lastname: Striker
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D018929:Cell Culture Techniques / Q000379:methods; D002460:Cell Line; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005920:Glomerular Mesangium / Q000503:physiopathology*; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D017526:Receptor, IGF Type 1 / Q000502:physiology; D012016:Reference Values; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D004791:Enzyme Inhibitors; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D020782:Matrix Metalloproteinases