Premium
IGF‐1 increases laminin, cyclin D1, and P21 Cip1 expression in glomerular mesangial cells: An investigation of the intracellular signaling pathway and cell‐cycle progression
Author(s) -
Jiang Yan,
Cheng Davis W.,
Levi Edi,
Singh Lalit P.
Publication year - 2006
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.20771
Subject(s) - protein kinase b , microbiology and biotechnology , cell cycle , cyclin d1 , biology , signal transduction , chemistry , endocrinology , medicine , cell , biochemistry
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 γ1 and β1 subunits ∼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‐3β), which inhibits its kinase activity. Laminin β1 is reduced significantly ( P < 0.03) by inhibitors of Akt and p38MAPK whereas laminin γ1 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‐3β, 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. J. Cell. Biochem. 98: 208–220, 2006. © 2006 Wiley‐Liss, Inc.