Advanced glycation end products increase collagen-specific chaperone protein in mouse diabetic nephropathy.
Advanced glycation end products (AGEs) appear to contribute to the diabetic complications. This study reports the inhibitory effect of OPB-9195 (OPB), an inhibitor of AGEs formation, and the role of a collagen-specific molecular chaperone, a 47-kDa heat shock protein (HSP47) in diabetic nephropathy. Transgenic mice carrying nitric-oxide synthase cDNA fused with insulin promoter (iNOSTg) leads to diabetes mellitus. The iNOSTg mice at 6 months of age represented diffuse glomerulosclerosis, and the expression of HSP47 was markedly increased in the mesangial area in parallel with increased expression of types I and IV collagens. OPB treatment ameliorated glomerulosclerosis in the iNOSTg mice associated with the decreased expression of HSP47 and types I and IV collagens. The expression of transforming growth factor-beta (TGF-beta) was increased in glomeruli of iNOSTg mice and decreased after treatment with OPB. To confirm these mechanisms, cultured mesangial cells were stimulated with AGEs. AGEs significantly increased the expression of HSP47, type IV collagen, and TGF-beta mRNA. Neutralizing antibody for TGF-beta inhibited the overexpression of both HSP47 and type IV collagen in vitro. In conclusion, AGEs increase the expression of HSP47 in association with collagens, both in vivo and in vitro. The processes may be mediated by TGF-beta.
Department of Clinical Biology and Medicine, Course of Biological Medicine, School of Medicine, The University of Tokushima, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
Seiji
S
Ohashi
Hideharu
H
Abe
Toshikazu
T
Takahashi
Yasuhiko
Y
Yamamoto
Masayoshi
M
Takeuchi
Hidenori
H
Arai
Kazuhiro
K
Nagata
Toru
T
Kita
Hiroshi
H
Okamoto
Hiroshi
H
Yamamoto
Toshio
T
Doi
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D003094:Collagen / Q000737:chemistry* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology*; D005920:Glomerular Mesangium / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors / Q000502:physiology*; D050958:HSP47 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism; D007328:Insulin / Q000235:genetics; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007834:Lasers; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D012260:Ribonucleases / Q000378:metabolism; D051785:Smad Proteins; D013830:Thiadiazoles / Q000494:pharmacology; D053778:Thiazolidines; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism
D001786:Blood Glucose; D004268:DNA-Binding Proteins; D017127:Glycation End Products, Advanced; D050958:HSP47 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D007328:Insulin; C105739:OPB 9195; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C494661:Serpinh1 protein, mouse; D051785:Smad Proteins; D013830:Thiadiazoles; D053778:Thiazolidines; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D003094:Collagen; D012260:Ribonucleases