title: Advanced glycation end-products induce basement membrane hypertrophy in endoneurial microvessels and disrupt the blood-nerve barrier by stimulating the release of TGF-β and vascular endothelial growth factor (VEGF) by pericytes.
abstract: OBJECTIVE
  The breakdown of the blood-nerve barrier (BNB) is considered to be a key step in diabetic neuropathy. Although basement membrane hypertrophy and breakdown of the BNB are characteristic features of diabetic neuropathy, the underlying pathogenesis remains unclear. The purpose of the present study was to identify the possible mechanisms responsible for inducing the hypertrophy of basement membrane and the disruption of the BNB after exposure to AGEs.
  
  
  METHODS
  The newly established human peripheral nerve microvascular endothelial cell (PnMEC) and pericyte cell lines were used to elucidate which cell types constituting the BNB regulate the basement membrane and to investigate the effect of AGEs on the basement membrane of the BNB using western blot analysis.
  
  
  RESULTS
  Fibronectin, collagen type IV and tissue inhibitor of metalloproteinase (TIMP-1) protein were produced mainly by peripheral nerve pericytes, indicating that the basement membrane of the BNB is regulated mainly by these cells. AGEs reduced the production of claudin-5 in PnMECs by increasing autocrine signalling through vascular endothelial growth factor (VEGF) secreted by the PnMECs themselves. Furthermore, AGEs increased the amount of fibronectin, collagen type IV and TIMP-1 in pericytes through a similar upregulation of autocrine VEGF and transforming growth factor (TGF)-β released by pericytes.
  
  
  CONCLUSIONS
  These results indicate that pericytes may be the main regulators of the basement membrane at the BNB. AGEs induce basement membrane hypertrophy and disrupt the BNB by increasing autocrine VEGF and TGF-β signalling by pericytes under diabetic conditions.
authors.affiliation: Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami kogushi, Ube, Yamaguchi 7558505, Japan.
authors.forename: F
authors.initials: F
authors.lastname: Shimizu
authors.forename: Y
authors.initials: Y
authors.lastname: Sano
authors.forename: H
authors.initials: H
authors.lastname: Haruki
authors.forename: T
authors.initials: T
authors.lastname: Kanda
mesh_terms: D001485:Basement Membrane / Q000187:drug effects / Q000473:pathology*; D049428:Blood-Nerve Barrier / Q000187:drug effects* / Q000503:physiopathology; D002478:Cells, Cultured; D062507:Claudin-5; D024141:Collagen Type IV / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000473:pathology; D005353:Fibronectins / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D006801:Humans; D006984:Hypertrophy; D008565:Membrane Proteins / Q000378:metabolism; D055806:Microvessels / Q000473:pathology*; D020286:Pericytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: C107466:CLDN5 protein, human; D062507:Claudin-5; D024141:Collagen Type IV; D005353:Fibronectins; D017127:Glycation End Products, Advanced; D008565:Membrane Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A