IGF-1 increases laminin, cyclin D1, and p21Cip1 expression in glomerular mesangial cells: an investigation of the intracellular signaling pathway and cell-cycle progression.
Insulin-like growth factor (IGF)-1 is accumulated in the diabetic kidney and is considered to be involved in the development of glomerular sclerosis. Here, we investigate IGF-1 regulation of laminin, an extracellular matrix (ECM) component, and cyclin D1 and p21Cip1, cell-cycle progression factor, expressions in glomerular mesangial cells. We show that IGF-1 increases the level of laminin gamma1 and beta1 subunits approximately 1.5- and 2.5-fold, respectively, in a time-dependent manner. IGF-1 also stimulates protein kinase Akt/PKB phosphorylation at Thr 308, which correlates with its activity, up to 24 h. The Akt activation is coupled with Ser 9 phosphorylation of its downstream target, glycogen synthase kinase-3beta (GSK-3beta), which inhibits its kinase activity. Laminin beta1 is reduced significantly (P < 0.03) by inhibitors of Akt and p38MAPK whereas laminin gamma1 is not affected. Surprisingly, IGF-1 activates the expression of both cyclin D1 and cell-cycle arrest factor, p21Cip1 parallely. Pharmacological inhibition of calcineurin by cyclosporin A blocks IGF-1-induced cyclin D1 and p21Cip1expression significantly (P < 0.05). IGF-1 enhances cellular metabolic activity and viability of rat mesangial cells; however, they are arrested at the G1 phase of cell cycle as revealed by the FACS analysis. These results indicate that IGF-1 mediates mesangial cell-cycle progression, hypertrophy, and ECM protein synthesis. The Akt/GSK-3beta, p38MAPK, and calcineurin pathways may play an important role in IGF-1 signaling, cell-cycle regulation, and matrix gene expression in mesangial cells leading to the development of diabetic glomerulopathy.
Jiang
Yan
Y
Departments of Internal Medicine, Nephrology and Physiology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Cheng
Davis W
DW
Levi
Edi
E
Singh
Lalit P
LP
D000818:Animals; D002453:Cell Cycle / Q000235:genetics*; D002460:Cell Line; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000235:genetics*; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D006984:Hypertrophy / Q000378:metabolism / Q000473:pathology; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000502:physiology; D007797:Laminin / Q000096:biosynthesis / Q000235:genetics*; D051381:Rats; D015398:Signal Transduction / Q000235:genetics*
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016326:Extracellular Matrix Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007797:Laminin; D019938:Cyclin D1; D007334:Insulin-Like Growth Factor I