title: Advanced-glycation-end-product-cholesterol-aggregated-protein accelerates the proliferation of mesangial cells mediated by transforming-growth-factor-beta 1 receptors and the ERK-MAPK pathway.
abstract: Hyperglycemia and hyperlipidemia are considered critical to the development of diabetic nephropathy. The aim of this study is to clarify the effect of cholesterol on advanced-glycation-end-products and the mechanisms behind the advanced-glycation-end-product-cholesterol-aggregated bovine serum albumin (BSA)-induced proliferation of mesangial cells. Mesangial cells were treated with advanced-glycation-end-product-cholesterol-aggregated-BSA, and RNA and protein were isolated. Cholesterol caused a 1.5-fold increase in fluorescent intensity and 2-fold increase in advanced-glycation-end-products in vitro. Pyridoxamine, aminoguanidine, and N-acetyl-l-cycteine suppressed the production of advanced-glycation-end-product-cholesterol-aggregated-BSA. Advanced-glycation-end-product-cholesterol-BSA was analyzed by matrix-assisted-laser-desorption/ionization-time of flight mass spectrometry, and peaks were found to shift toward a higher mass. Advanced-glycation-end-product-cholesterol-aggregated-BSA induced overexpression of the mRNA of transforming growth factor-beta1, collagen type 1, collagen type 4 and receptor for advanced-glycation-end-products, and the proliferation of mesangial cells. The injection of advanced-glycation-end-product-cholesterol-aggregated-BSA caused glomerular changes and albuminuria in non-diabetic mice. A transforming-growth-factor-beta receptor 1 kinase inhibitor or Mitogen-activated-Protein-Kinase/Extracellular-Signal-regulated-Kinase kinase (ERK) inhibitor (U-0126) suppressed the proliferation of mesangial cells induced by advanced-glycation-end-product-cholesterol-aggregated-BSA dose-dependently. U-0126 inhibited the phosphorylation of ERK1/2 in advanced-glycation-end-product-cholesterol-aggregated-BSA treated mesangial cells. These findings suggested that cholesterol promotes the formation of advanced-glycation-end-products-protein and that advanced-glycation-end-product-cholesterol-aggregated protein stimulates mesangial cells to proliferate via transforming-growth-factor-beta receptors and the ERK-MAPK pathway in diabetic glomeruli.
authors: Laboratory of Pharmacobiology and Therapeutics, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tenpaku-ku, Nagoya 468-8503, Japan. y-hirasawa@nbr.co.jp
authors: Yasushi
authors: Y
authors: Hirasawa
authors: Takayuki
authors: T
authors: Sakai
authors: Masanori
authors: M
authors: Ito
authors: Hiromitsu
authors: H
authors: Yoshimura
authors: Yibin
authors: Y
authors: Feng
authors: Tadashi
authors: T
authors: Nagamatsu
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D002784:Cholesterol / Q000494:pharmacology*; D003920:Diabetes Mellitus / Q000378:metabolism / Q000473:pathology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D050527:Mesangial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000737:chemistry* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics
chemical_list: D002070:Butadienes; D017127:Glycation End Products, Advanced; D009570:Nitriles; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C113580:U 0126; D012710:Serum Albumin, Bovine; D002784:Cholesterol; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases