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.
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.
Division of Nephrology and Hypertension, University of Miami Miller School of Medicine, 1600 Northwest 10th Avenue, Room 7168, Florida 33136, USA. afornoni@med.miami.edu
Alessia
A
Fornoni
Steven A
SA
Rosenzweig
Oliver
O
Lenz
Ana
A
Rivera
Gary E
GE
Striker
Sharon J
SJ
Elliot
D000818:Animals; D002460:Cell Line; D003928:Diabetic Nephropathies / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D005920:Glomerular Mesangium / Q000473:pathology; D005921:Glomerulonephritis / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000378:metabolism*; D050527:Mesangial Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation
D055504:Insulin Receptor Substrate Proteins; D018971:Insulin-Like Growth Factor Binding Protein 2; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D005947:Glucose