title: Advanced glycation end products induce glomerular endothelial cell hyperpermeability by upregulating matrix metalloproteinase activity.
abstract: The present study aimed to investigate the effects of advanced glycation end‑products (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 MMP‑2/9 inhibitor (2R)‑2‑((4‑biphenyl sulfony‑l)amino)‑3‑phenylproprionic acid) (BiPs). Expression of the TJ proteins occludin and claudin‑5 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 MMP‑2 and MMP‑9 were assayed using gelatin zymography. The results indicated that AGE‑treated cultures significantly reduced occludin and claudin‑5 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 FITC‑dextran. Treatment with AGEs evoked a dose‑ and time‑dependent upregulation of MMP‑2 and MMP‑9. However, co‑administration of AGEs and BiPS, an inhibitor of MMP‑2/MMP‑9, inhibited the downregulation of occludin and claudin‑5, with a concomitant reversal of GEnC monolayer hyperpermeability. In conclusion, AGEs promoted glomerular hyperpermeability in vitro by the MMP‑mediated 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.
authors: Department of Nephrology, Affiliated Hospital of Qinghai University, Xining, Qinghai 810001, P.R. China.
authors: Pengli
authors: P
authors: Luo
authors: Department of Nephrology, The Third Afﬁliated Hospital of Sun Yat‑Sen University, Guangzhou, Guangdong 510660, P.R. China.
authors: Hui
authors: H
authors: Peng
authors: Department of Nephrology, The Third Afﬁliated Hospital of Sun Yat‑Sen University, Guangzhou, Guangdong 510660, P.R. China.
authors: Canming
authors: C
authors: Li
authors: Department of Nephrology, The Third Afﬁliated Hospital of Sun Yat‑Sen University, Guangzhou, Guangdong 510660, P.R. China.
authors: Zengchun
authors: Z
authors: Ye
authors: Department of Nephrology, The Third Afﬁliated Hospital of Sun Yat‑Sen University, Guangzhou, Guangdong 510660, P.R. China.
authors: Hua
authors: H
authors: Tang
authors: Department of Nephrology, The Second Afﬁliated Hospital of Sun Yat‑Sen University, Guangzhou, Guangdong 510000, P.R. China.
authors: Ying
authors: Y
authors: Tang
authors: Department of Nephrology, The Third Afﬁliated Hospital of Sun Yat‑Sen University, Guangzhou, Guangdong 510660, P.R. China.
authors: Cailian
authors: C
authors: Chen
authors: Department of Nephrology, The Third Afﬁliated Hospital of Sun Yat‑Sen University, Guangzhou, Guangdong 510660, P.R. China.
authors: Tanqi
authors: T
authors: Lou
mesh_terms: D000818:Animals; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000187:drug effects*; D062507:Claudin-5 / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D062793:Occludin / Q000378:metabolism; D051381:Rats; D019108:Tight Junctions / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D062507:Claudin-5; D017127:Glycation End Products, Advanced; D061965:Matrix Metalloproteinase Inhibitors; D062793:Occludin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9