Advanced glycation end product-induced apoptosis and overexpression of vascular endothelial growth factor and monocyte chemoattractant protein-1 in human-cultured mesangial cells.
Advanced glycation end products (AGE) have been implicated in the pathogenesis of glomerulosclerosis in diabetes. However, their involvement in the development of the early phase of diabetic nephropathy has not been fully elucidated. We investigated the effects of AGE on growth and on vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP-1) expression in human cultured mesangial cells. We prepared three immunochemically distinct AGE by incubating bovine serum albumin (BSA) with glucose, glyceraldehyde, or glycolaldehyde. When human mesangial cells were cultured with various types of AGE-BSA, viable cell numbers as well as DNA syntheses were significantly decreased. All of the AGE-BSA were found to significantly increase p53 and Bax protein accumulations and subsequently induce apoptotic cell death in mesangial cells. An antioxidant, N-acetylcysteine, significantly prevented the AGE-induced apoptotic cell death in mesangial cells. Human mesangial cells stimulated prostacyclin production by co-cultured glomerular endothelial cells. Furthermore, various types of AGE-BSA were found to up-regulate the levels of mRNAs for VEGF and stimulate the secretion of VEGF and MCP-1 proteins in mesangial cells. The results suggest that AGE disturbed glomerular homeostasis by inducing apoptotic cell death in mesangial cells and elicited hyperfiltration and microalbuminuria by stimulating the secretion of VEGF and MCP-1 proteins, thereby being involved in the pathogenesis of the early phase of diabetic nephropathy.
Yamagishi
Sho-ichi
S
Division of Endocrinology and Metabolism, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan. shoichi@med.kurume-u.ac.jp
Inagaki
Yosuke
Y
Okamoto
Tamami
T
Amano
Shinjiro
S
Koga
Kohachiro
K
Takeuchi
Masayoshi
M
Makita
Zenji
Z
D000111:Acetylcysteine / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D002455:Cell Division; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics*; D018920:Coculture Techniques; D003928:Diabetic Nephropathies / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000235:genetics*; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000502:physiology*; D006801:Humans; D008222:Lymphokines / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D018932:Chemokine CCL2; D016228:Endothelial Growth Factors; D017127:Glycation End Products, Advanced; D008222:Lymphokines; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000111:Acetylcysteine