title: Ranirestat has a stronger inhibitory activity on aldose reductase and suppresses inflammatory reactions in high glucose-exposed endothelial cells.
abstract: Under diabetic conditions, glucose is converted to sorbitol via aldose reductase, whose process could contribute to diabetic vascular complications. However, effects of aldose reductase inhibitors are modest in diabetic patients. This may be attributed to weak inhibitory activity of aldose reductase inhibitors. We compared effects of ranirestat on endothelial cell damage with those of epalrestat.
  
  
  
  Intracellular formations of sorbitol and superoxide were measured by liquid chromatography-mass spectrometry-mass spectrometry and dihydroethidium staining, respectively. Vascular cell adhesion molecule-1 gene expression was analysed by reverse transcription polymerase chain reaction. THP-1 cell adhesion to human umbilical vein endothelial cells was evaluated using a fluorescent probe.
  
  
  
  High glucose significantly increased sorbitol levels, superoxide generation and vascular cell adhesion molecule-1 mRNA levels in, and THP-1 cell adhesion to, human umbilical vein endothelial cells, all of which were prevented by 500 nM ranirestat, but not epalrestat except for superoxide production.
  
  
  
  Our present results suggest that ranirestat has a stronger inhibitory activity on aldose reductase than epalrestat and suppresses inflammatory reactions in high glucose-exposed human umbilical vein endothelial cells.
authors.affiliation: Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishibashi
authors.affiliation: Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Matsui
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd, Osaka, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Matsumoto
authors.affiliation: Drug Development Division, Sumitomo Dainippon Pharma Co., Ltd, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kato
authors.affiliation: Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan shoichi@med.kurume-u.ac.jp.
authors.forename: Sho-Ichi
authors.initials: S
authors.lastname: Yamagishi
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005947:Glucose / Q000633:toxicity*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012236:Rhodanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013012:Sorbitol / Q000378:metabolism; D013141:Spiro Compounds / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D053778:Thiazolidines / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D011719:Pyrazines; D013141:Spiro Compounds; D053778:Thiazolidines; D019010:Vascular Cell Adhesion Molecule-1; D013481:Superoxides; C038131:epalrestat; D013012:Sorbitol; D012236:Rhodanine; D000449:Aldehyde Reductase; D005947:Glucose; C115070:ranirestat
keywords: Aldose reductase; endothelial cells; inflammation; oxidative stress