Advanced glycation end products increase collagen-specific chaperone protein in mouse diabetic nephropathy.

Abstract	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.
Authors	Seiji Ohashi, Hideharu Abe, Toshikazu Takahashi, Yasuhiko Yamamoto, Masayoshi Takeuchi, Hidenori Arai, Kazuhiro Nagata, Toru Kita, Hiroshi Okamoto, Hiroshi Yamamoto, Toshio Doi
Journal	The Journal of biological chemistry (J Biol Chem) Vol. 279 Issue 19 Pg. 19816-23 (May 07 2004) ISSN: 0021-9258 [Print] United States
PMID	15004023 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Blood Glucose DNA-Binding Proteins Glycation End Products, Advanced HSP47 Heat-Shock Proteins Heat-Shock Proteins Insulin OPB 9195 Oligonucleotides, Antisense RNA, Messenger RNA, Small Interfering Serpinh1 protein, mouse Smad Proteins Thiadiazoles Thiazolidines Trans-Activators Transforming Growth Factor beta Collagen Ribonucleases
Topics	Animals Blood Glucose (metabolism) Blotting, Western Cells, Cultured Collagen (chemistry, metabolism) DNA-Binding Proteins (metabolism) Diabetic Nephropathies (metabolism, pathology) Glomerular Mesangium (metabolism) Glycation End Products, Advanced (antagonists & inhibitors, physiology) HSP47 Heat-Shock Proteins Heat-Shock Proteins (metabolism) Insulin (genetics) Kidney (metabolism, pathology) Lasers Male Mice Mice, Inbred C57BL Mice, Transgenic Microscopy, Fluorescence Oligonucleotides, Antisense (pharmacology) Polymerase Chain Reaction Promoter Regions, Genetic RNA, Messenger (metabolism) RNA, Small Interfering (metabolism) Ribonucleases (metabolism) Smad Proteins Thiadiazoles (pharmacology) Thiazolidines Time Factors Trans-Activators (metabolism) Transfection Transforming Growth Factor beta (metabolism)

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