This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fornoni, A. Articles by Elliot, S. J. Search for Related Content PubMed PubMed Citation Articles by Fornoni, A. Articles by Elliot, S. J.

Low Insulin-Like Growth Factor Binding Protein-2 Expression Is Responsible for Increased Insulin Receptor Substrate-1 Phosphorylation in Mesangial Cells from Mice Susceptible to Glomerulosclerosis

Division of Nephrology and Hypertension (A.F., O.L., S.J.E.) and Vascular Biology Institute (O.L., A.R., G.E.S., S.J.E.), University of Miami Miller School of Medicine, Miami, Florida 33136; and Department of Cell and Molecular Pharmacology and Experimental Therapeutics and Hollings Cancer Center (S.A.R.), Medical University of South Carolina, Charleston, South Carolina 29425

Address all correspondence and requests for reprints to: Alessia Fornoni, Division of Nephrology and Hypertension, University of Miami Miller School of Medicine, 1600 Northwest 10th Avenue, Room 7168, Miami, Florida 33136. E-mail: afornoni{at}med.miami.edu.

Mesangial cells (MC) isolated from glomerulosclerosis-prone ragged, olygosyndactilism, pintail (ROP) mice retain a stable phenotype after exposure to elevated glucose concentrations, whereas MC from glomerulosclerosis-resistant C57BL/6 (C) mice do not. In NOD and db/db mice, the stable phenotype induced by diabetes consists of autocrine activation of the IGF-I signaling pathway. We hypothesized that high ambient glucose activates the IGF-I pathway in ROP but not in C MC. MC were propagated in either 6 or 25 mM glucose. Isolated murine glomeruli were used to confirm in vitro experiments. 25 mM glucose induced increased insulin receptor substrate (IRS)-1 phosphorylation in ROP but not C MC. However, IGF-I, IGF-I receptor, and IRS-1 protein levels were induced by exposure to 25 mM glucose in both cell lines. This occurred without a change in IGF-I binding sites, suggesting a role for IGF binding protein (IGFBP). ROP MC and glomeruli expressed less IGFBP-2 than C MC and glomeruli. Addition of exogenous IGFBP-2 partially blunted the effect of 25 mM glucose on IRS-1 phosphorylation in ROP MC. Renal biopsies from patients with diabetic nephropathy also showed markedly decreased IGFBP-2 expression when compared with patients without nephropathy. In summary, glucose induces IRS-1 phosphorylation in MC isolated from ROP mice susceptible to glomerulosclerosis. IGFBP-2 expression was low in ROP MC and glomeruli from patients with diabetic nephropathy, suggesting that this may represent a new marker of susceptibility to diabetic nephropathy. Finally, addition of exogenous IGFBP-2 in ROP MC partially blunted the effect of high glucose on IRS-1 phosphorylation and might have a protective role.

This article has been cited by other articles:

				S. J. Elliot, M. Karl, M. Berho, X. Xia, S. Pereria-Simon, D. Espinosa-Heidmann, and G. E. Striker Smoking Induces Glomerulosclerosis in Aging Estrogen-Deficient Mice through Cross-Talk between TGF-beta1 and IGF-I Signaling Pathways J. Am. Soc. Nephrol., December 1, 2006; 17(12): 3315 - 3324. [Abstract] [Full Text] [PDF]