Proximal tubular epithelial cell integrins respond to high glucose by altered cell-matrix interactions and differentially regulate matrixin expression

Panagiotis M. Karamessinis, Athina K. Tzinia, Paraskevi V. Kitsiou, William G. Stetler-Stevenson, Alfred F. Michael, Wei Wei Fan, Bing Zhou, Lukas H. Margaritis, Effie C. Tsilibary

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26 Scopus citations


Thickening of the tubular basement membrane (TBM) occurs in diabetic nephropathy, but the effects of high glucose on the functional aspects of proximal tubular epithelial cells are not clearly understood. In the present study, we examined the effects of elevated glucose concentrations on (a) integrin expression by human proximal tubular epithelial cells (HK-2) and integrin-mediated interactions with type IV collagen (collV) and laminin, major components of TBM; (b) the expression of matrixins/matrix metalloproteinases (MMPs), which is regulated by integrins; and (c) the expression of tissue inhibitors of metalloproteinases (TIMPs). HK-2 cells cultured in 25 mM glucose underwent a reduction of the expression of α3, β1, αvβ3, and α5 integrin subunits, with a concomitant increase of the α2 subunit, compared with cells grown in 5 mM glucose. Adhesion experiments demonstrated that high glucose led to increased cell adhesion on either collV or laminin. Experiments of competition of adhesion using anti-integrin antibodies indicated that HK-2 cells in 5 mM glucose used mainly αvβ3 and α5β1 integrins to adhere to collV, whereas in 25 mM glucose they additionally used a2β1. In the case of laminin, a β1-mediated adhesion was observed when HK-2 cells were in 5 mM glucose, whereas in 25 mM glucose, a2β1 and αvβ3 were also involved. Elevated glucose concentrations resulted in decreased expression of MMP-9 and MMP-2, whereas an increase in TIMP-1 and a decrease in TIMP-2 expression were observed. We also examined which integrins mediated the expression and secretion of matrixins MMP-2 and MMP-9. Ligation of α3β1 with mAbs resulted in induction of MMP-2 expression and secretion, whereas antibody ligation of αvβ3 led to down-regulation of MMP-9. The above data implicate integrins of proximal tubular epithelial cells in the regulation of MMPs and in the development of TBM thickening in diabetic nephropathy.

Original languageEnglish (US)
Pages (from-to)1081-1093
Number of pages13
JournalLaboratory Investigation
Issue number8
StatePublished - Aug 2002

Bibliographical note

Funding Information:
Supported by National Institutes of Health (Grant AI0708) and by the Greek GSRT/PENED-99 (Grant 174ED). Address reprint requests to: Dr. Effie C. Tsilibary, Institute of Biology, National Center for Scientific Research “Demokritos”, 15310 Agia Paraskevi, Athens, Greece. E-mail:

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