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.
JournalEuropean journal of pharmacology
Eur J Pharmacol (1879-0712)
Laboratory of Pharmacobiology and Therapeutics, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tenpaku-ku, Nagoya 468-8503, Japan. y-hirasawa [at] nbr.co.jp
Eur J Pharmacol. 2011 Dec;672(1-3):159-68
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