IGF-1 increases laminin, cyclin D1, and P21Cip1 expression in glomerular mesangial cells: An investigation of the intracellular signaling pathway and cell-cycle progression

✍ Scribed by Yan Jiang; Davis W. Cheng; Edi Levi; Lalit P. Singh

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 404 KB
• Volume: 98
• Category: Article
• ISSN: 0730-2312
• DOI: 10.1002/jcb.20771

✦ Synopsis

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 p21 Cip1 , cell-cycle progression factor, expressions in glomerular mesangial cells. We show that IGF-1 increases the level of laminin g1 and b1 subunits $1.5and 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-3b), which inhibits its kinase activity. Laminin b1 is reduced significantly (P < 0.03) by inhibitors of Akt and p38MAPK whereas laminin g1 is not affected. Surprisingly, IGF-1 activates the expression of both cyclin D1 and cell-cycle arrest factor, p21 Cip1 parallely. Pharmacological inhibition of calcineurin by cyclosporin A blocks IGF-1-induced cyclin D1 and p21 Cip1 expression significantly (P < 0.05). IGF-1 enhances cellular metabolic activity and viability of rat mesangial cells; however, they are arrested at the G 1 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-3b, 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.