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

Abstract

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.

Insulin-like growth factor-1 promotes cell cycle progression via upregulation of cyclin D1 expression through the phosphatidylinositol 3-kinase/nuclear factor-κB signaling pathway in FRTL thyroid cells

“…This indicates that IGF-1 promotes cell entry into S phase in thyroid cells. Our results were not consistent with those of a study of glomerular mesangial cells, which showed that IGF-1 increased cyclin D1 levels to promote G 0 /G 1 progression but did not induce G 1 to S phase transition [17] . This discrepancy may be a result of the different cell types used in the two studies.…”

PPAR-Alpha Agonist Fenofibrate Induces Renal CYP Enzymes and Reduces Blood Pressure and Glomerular Hypertrophy in Zucker Diabetic Fatty Rats

“…The overexpression of cyclin D1, a key regulator of G1-to-S phase progression of the cell cycle, has been reported in glomerular and renal hypertrophy caused by hyperglycemia in diabetes [20, 21]. We next sought to determine the effect of fenofibrate on protein expression of cyclin D1 in the kidney.…”

“…An increase in expression of cyclin D1 has been reported in renal and glomerular hypertrophy in vivo and in mesangial cell hypertrophy in culture [20, 21]. Whole-kidney and glomerular hypertrophy caused by hyperglycemia is associated with specific G1 phase cell-cycle events: an early and sustained increase in the expression of cyclin D1 and activation of cyclin D1-cdk4 complexes, but no change in the expression of cyclin E1 or cdk2 activity [20].…”

Akt1 in Endothelial Cell and Angiogenesis

“…5 Another recent report also suggests that Akt can directly regulate the expression of laminin by mesangial cells in response to insulin-like growth factor 1. 69 It was recently shown that deficiency of Akt1, but not Akt2, impairs revascularization and repair of the tissues followed by hind limb ischemia. 20 VEGF production stimulated by hypoxia in this model is anticipated to be defective in Akt1 -/-mice, since Akt is directly involved in the regulation of VEGF expression.…”