Advanced glycation end products induce glomerular endothelial cell hyperpermeability by upregulating matrix metalloproteinase activity

Author：

Publisher： Spandidos Publications

E-ISSN： 1791-3004|11|6|4447-4453

ISSN： 1791-2997

Source： Molecular Medicine Reports, Vol.11, Iss.6, 2015-01, pp. : 4447-4453

Disclaimer: Any content in publications that violate the sovereignty, the constitution or regulations of the PRC is not accepted or approved by CNPIEC.

Previous Menu Next

Abstract

The present study aimed to investigate the effects of advanced glycation endproducts (AGEs) on the permeability of glomerular endothelial cells (GEnCs) and determine whether enhanced permeability was due to degradation of tight junction (TJ) complexes by matrix metalloproteinases (MMPs). Cultured monolayers of GEnCs were exposed to AGEs at different doses and treatment durations in the presence or absence of the organic MMP2/9 inhibitor (2R)2((4biphenyl sulfonyl)amino)3phenylproprionic acid) (BiPs). Expression of the TJ proteins occludin and claudin5 was determined by western blot analysis and immunofluorescence, while the permeability of the GEnCs was measured using transendothelial electrical resistance and by diffusion of 4 kDa fluorescein isothiocyanate (FITC)dextran. The activities of MMP2 and MMP9 were assayed using gelatin zymography. The results indicated that AGEtreated cultures significantly reduced occludin and claudin5 immunoreactivity. Similarly, the surface expression of these proteins was significantly reduced and rows of TJs which normally connect endothelial cells became discontinuous or fractured following AGE exposure. Disruption of TJs was accompanied by significantly reduced transendothelial resistance and hyperpermeability to FITCdextran. Treatment with AGEs evoked a dose and timedependent upregulation of MMP2 and MMP9. However, coadministration of AGEs and BiPS, an inhibitor of MMP2/MMP9, inhibited the downregulation of occludin and claudin5, with a concomitant reversal of GEnC monolayer hyperpermeability. In conclusion, AGEs promoted glomerular hyperpermeability in vitro by the MMPmediated disruption of TJs. Chronic elevation of endothelial cell AGEs in diabetes mellitus may contribute to glomerular hyperpermeability by inducing the overexpression of MMPs, which degrade TJs, leading to proteinuria.