Abstract | BACKGROUND: We have shown previously that OPB-9195, a novel inhibitor of advanced glycation end products (AGE), significantly prevented renal tubular injury and tubulointerstitial fibrosis in spontaneous diabetic rats. However, the molecular mechanisms underlying this have not been fully elucidated. METHODS: RESULTS: When these AGE-BSA were administered to tubular cells, each of them increased generation of intracellular ROS. All of the AGE-BSA, but not non-glycated BSA, were found to induce statistically significant decreases in de novo protein synthesis and PGE2 secretion by tubular cells. Furthermore, AGE-BSA up-regulated the levels of mRNAs for TGF-beta in tubular cells. The structural epitope designated glucose-derived AGE was found to have the greatest cytopathic effects on tubular cells. These AGE-induced inhibition of protein synthesis and PGE2 secretion as well as the up-regulation of TGF-beta mRNA were found to be completely prevented by N-acetylcysteine. Furthermore, H2O2 was shown to inhibit protein synthesis and PGE2 secretion by proximal tubular cells in a dose-dependent manner. CONCLUSION: The results suggest that AGE inhibits de novo protein synthesis and stimulates TGF-beta mRNA expression in proximal tubular epithelial cells through overgeneration of intracellular ROS. Thus, AGE are involved in the pathogenesis of tubular injury in diabetic nephropathy.
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Authors | Sho-Ichi Yamagishi, Yosuke Inagaki, Tamami Okamoto, Shinjiro Amano, Kohachiro Koga, Masayoshi Takeuchi |
Journal | Kidney international
(Kidney Int)
Vol. 63
Issue 2
Pg. 464-73
(Feb 2003)
ISSN: 0085-2538 [Print] United States |
PMID | 12631112
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Glycation End Products, Advanced
- Protein Synthesis Inhibitors
- RNA, Messenger
- Reactive Oxygen Species
- Transforming Growth Factor beta
- advanced glycation end products-bovine serum albumin
- Serum Albumin, Bovine
- Hydrogen Peroxide
- Leucine
- Dinoprostone
- Thymidine
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Topics |
- Cells, Cultured
- Diabetes Mellitus
(blood)
- Dinoprostone
(metabolism)
- Glycation End Products, Advanced
(pharmacology)
- Humans
- Hydrogen Peroxide
(pharmacology)
- Intracellular Membranes
(metabolism)
- Kidney Tubules, Proximal
(cytology, drug effects, metabolism)
- Leucine
(metabolism)
- Protein Synthesis Inhibitors
(pharmacology)
- RNA, Messenger
(metabolism)
- Reactive Oxygen Species
- Serum Albumin, Bovine
(pharmacology)
- Thymidine
(metabolism)
- Transforming Growth Factor beta
(genetics, metabolism)
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