| Autor: |
Tack, Ivan, Elliot, Sharon J., Potier, Mylene, Rivera, Ana, Striker, Gary E., Striker, Liliane J. |
| Předmět: |
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| Zdroj: |
Diabetes; Jan2002, Vol. 51 Issue 1, p182-188, 7p, 4 Diagrams, 4 Graphs, 2 Maps |
| Abstrakt: |
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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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