TY - JOUR
T1 - Effects of high glucose on integrin activity and fibronectin matrix assembly by mesangial cells
AU - Miller, Charles G.
AU - Pozzi, Ambra
AU - Zent, Roy
AU - Schwarzbauer, Jean E.
PY - 2014
Y1 - 2014
N2 - The filtration unit of the kidney is the glomerulus, a capillary network supported by mesangial cells and extracellular matrix (ECM). Glomerular function is compromised in dia betic nephropathy (DN) by uncontrolled buildup of ECM, especially type IV collagen, which progressively occludes the capillaries. Increased levels of the ECM protein fibronectin (FN) are also present; however, its role in DN is unknown. Mesangial cells cultured under high glucose conditions provide a model system for studying the effect of elevated glucose on deposition of FN and collagen IV. Imaging of mesangial cell cultures and analysis of deter gent-insoluble matrix show that, under high glucose conditions, mesangial cells assembled significantly more FN matrix, independent of FN protein levels. High glucose conditions in duced protein kinase C-dependent β1 integrin activation, and FN assembly in normal glucose was increased by stimulation of integrin activity with Mn2+. Collagen IV incorporation into the matrix was also increased under high glucose conditions and colocalized with FN fibrils. An inhibitor of FN matrix assembly prevented collagen IV deposition, demonstrating depen dence of collagen IV on FN matrix. We conclude that high glucose induces FN assembly, which contributes to collagen IV accumulation. Enhanced assembly of FN might facilitate dysregulated ECM accumulation in DN.
AB - The filtration unit of the kidney is the glomerulus, a capillary network supported by mesangial cells and extracellular matrix (ECM). Glomerular function is compromised in dia betic nephropathy (DN) by uncontrolled buildup of ECM, especially type IV collagen, which progressively occludes the capillaries. Increased levels of the ECM protein fibronectin (FN) are also present; however, its role in DN is unknown. Mesangial cells cultured under high glucose conditions provide a model system for studying the effect of elevated glucose on deposition of FN and collagen IV. Imaging of mesangial cell cultures and analysis of deter gent-insoluble matrix show that, under high glucose conditions, mesangial cells assembled significantly more FN matrix, independent of FN protein levels. High glucose conditions in duced protein kinase C-dependent β1 integrin activation, and FN assembly in normal glucose was increased by stimulation of integrin activity with Mn2+. Collagen IV incorporation into the matrix was also increased under high glucose conditions and colocalized with FN fibrils. An inhibitor of FN matrix assembly prevented collagen IV deposition, demonstrating depen dence of collagen IV on FN matrix. We conclude that high glucose induces FN assembly, which contributes to collagen IV accumulation. Enhanced assembly of FN might facilitate dysregulated ECM accumulation in DN.
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U2 - 10.1091/mbc.E14-03-0800
DO - 10.1091/mbc.E14-03-0800
M3 - Article
C2 - 24943838
AN - SCOPUS:84905980583
SN - 1059-1524
VL - 25
SP - 2342
EP - 2350
JO - Molecular biology of the cell
JF - Molecular biology of the cell
IS - 16
ER -