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.

Rutin Prevents High Glucose-Induced Renal Glomerular Endothelial Hyperpermeability by Inhibiting the ROS/Rhoa/ROCK Signaling Pathway

“…Hyperglycemia (HG) can rapidly increase systemic endothelial and glomerular barrier permeabilities in vivo. Such changes have also been amply demonstrated in the absence of insulin in endothelial monolayers in vitro [3][4][5]. Therefore, the endothelium plays an important role in the glomerular barrier upon HG [1,6].…”

Mdia1 is Crucial for Advanced Glycation End Product-Induced Endothelial Hyperpermeability

“…Microvascular barrier dysfunction and endothelial hyperpermeability leading to tissue edema and organ dysfunction are critical in the pathogenesis of these diseases. Although several studies have reported that AGEs contribute to elevated vascular endothelial monolayer permeability and microvascular permeability [2, 21, 25, 26], the mechanisms involved in these processes are complex and remain to be determined. Our study first confirmed the participation of mDia1 in endothelial hyperpermeability in response to AGEs.…”

Extracellular matrix remodeling and vascular complications in type1 diabetes

“…Therefore, MMPs have their own inhibitors, TIMPs. 56,57 An overview of TIMPs and their specific MMP substrates is shown in Table 1.2. TIMPs regulate cell functions through MMP-dependent as well as MMP-independent mechanisms, including cell proliferation, apoptosis and differentiation.…”

“…52 Literature provides lots of evidence that AGEs are able to induce MMP production. 29,[53][54][55][56][57][58][59][60][61][62][63][64][65][66] In vitro studies have shown AGEinduced MMP expression in various cells that are associated with vascular complications 29,57,62,65 We studied associations between circulating levels of proteinbound N ε -(carboxymethyl)lysine (CML), N ε -(carboxyethyl)lysine (CEL), 5-hydro-5methylimidazolone (MG-H1), pentosidine and MMP-1, -2, -3, -9, and -10, and TIMP-1. We showed that CML, an extracellular AGE and a major ligand of the receptor of AGE (RAGE), was positively associated with circulating MMP-2 and inversely with MMP-9 after adjustment for potential confounders.…”

“…AGEs are a heterogeneous group of glucose-modified proteins and AGE-induced MMP expression has been published previously. 29,[53][54][55][56][57][58][59][60][61][62][63][64][65][66] We determined serum levels of CML, CEL, MG-H1 and pentosidine in the PROFIL study and investigated associations between these AGEs and the markers of the MMP-TIMP system. In addition to the remarks regarding the markers of the MMP-TIMP system, it might be that the circulating levels do not truly reflect tissue levels of AGEs.…”