Glucose-induced changes in integrins and matrix-related functions in cultured human glomerular epithelial cells.
In cultured human glomerular epithelial cells (HGEC), 25 mM glucose resulted in decreased expression of alpha(3)-, alpha(2)-, and beta(1)-integrins and increased expression of alpha(5)- and alpha(v)beta(3)-integrins. This change was accompanied by decreased binding of HGEC to type IV collagen. In the presence of normal (5 mM) glucose concentration, cell binding to type IV collagen was primarily mediated by alpha(2)beta(1)- and alpha(5)beta(1)-integrins, as indicated by experiments in which cell adhesion to type IV collagen was competed by specific anti-integrin monoclonal antibodies. In the presence of high (25 mM) glucose, the upregulated alpha(5)- and alpha(v)beta(3)-integrins were mainly involved in cell binding to type IV collagen. Furthermore, high glucose decreased expression of matrix metalloproteinase-2 (MMP-2), a collagenase regulated in part by alpha(3)beta(1)-integrin, as suggested by the use of ligand-mimicking antibodies against these integrins, which resulted in release of increased amounts of MMP-2 in the culture medium. Finally, tissue inhibitor of metalloproteinase-2, the specific inhibitor of MMP-2, was upregulated in high glucose and could contribute to matrix accumulation. These changes could help explain basement membrane thickening in diabetes.
Kitsiou
Paraskevi V
PV
Institute of Biology, National Center for Scientific Research Demokritos, 15310 Agia Paraskevi, Athens, Greece. pkit@mail.demokritos.gr
Tzinia
Athina K
AK
Stetler-Stevenson
William G
WG
Michael
Alfred F
AF
Fan
Wei-Wei
WW
Zhou
Bing
B
Tsilibary
Effie C
EC
D001485:Basement Membrane / Q000378:metabolism; D002448:Cell Adhesion; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000209:etiology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000166:cytology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
D024141:Collagen Type IV; D016023:Integrins; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D005947:Glucose