C-peptide induces human renal mesangial cell proliferation in vitro, activating Src-kinase, PI-3 kinase and ERK1/2

Background: Elevated levels of C-peptide have been found in patients with insulin resistance and early type 2 diabetes. These patients are at greater risk to develop micro- and macrovascular complications. Since diabetic nephropathy involves glomerular hyperproliferation, the present study evaluates the role of C-peptide on human renal mesangial cell proliferation. Methods and results: C-peptide induces proliferation of human renal mesangial cells in a concentration-dependent manner with a maximal 2.6 +/- 0.4-fold induction at 10 nmol/L (P < 0.05 compared with unstimulated cells; n = 6), as revealed by [3H]-thymidine incorporation experiments. The proliferative effect of C-peptide is prevented by Src-kinase inhibitor-PP2, PI-3 kinase inhibitor-LY294002, and the ERK1/2 inhibitor-U126. Moreover, C-peptide induces phosphorylation of Src, as well as activation of PI-3 kinase and ERK1/2. Furthermore, C-peptide induces cyclin D1 expression as well as phosphorylation of retinoblastoma protein (Rb). Conclusions: These results demonstrate an active role of C-peptide on the proliferation of human renal mesangial cells in vitro involving PI-3 kinase and MAP kinase signaling pathways, suggesting a possible role of C-peptide in glomerular hyperproliferation in patients with diabetic nephropathy. (C) 2012 Elsevier Ireland Ltd. All rights reserved.