title: YM440, a novel hypoglycemic agent, protects against nephropathy in Zucker fatty rats via plasma triglyceride reduction.
abstract: The novel hypoglycemic agent, YM440 ((Z)-1,4-bis{4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl) methyl] phenoxy}but-2-ene) is a ligand of the peroxisome proliferator-activated receptor, (PPAR) gamma. YM440 has been shown to counteract insulin resistance in diabetic rodent models. However, it is not clear whether this compound has a significant effect on hyperlipidemia in vivo. Hyperlipidemia has been reported to be a risk factor for the early development of renal disease. The aim of this study is to examine the effects of chronic treatment with YM440 on hyperlipidemia and renal injury in obese Zucker fatty (ZF) rats. Treatment of 8-week-old ZF rats with YM440 (100 mg/kg/day) for 16 weeks decreased plasma triglyceride and cholesterol concentrations. YM440 markedly reduced the rate of progression of both albuminuria and proteinuria. YM440 normalized urinary N-acetyl-beta-D-glucosaminidase (NAG) activity, which is a marker for renal proximal tubular damage, and ameliorated the rise in systolic blood pressure compared to the vehicle control. YM440 also blocked the development of nephromegaly. Histological analyses revealed that both glomerular area expansion and tubular cast accumulation gradually lessened in YM440-treated ZF rats. Regression analyses between the plasma triglyceride levels and the renal parameters (urinary protein excretion and albumin excretion) indicated that the renal parameters correlated positively with the plasma triglyceride levels. In conclusion, the hypolipidemic effects of YM440 prevent renal injury in ZF rats. YM440 might be useful for preventing the early development of diabetic nephropathy in subjects with type 2 diabetes by ameliorating metabolic control problems.
authors.affiliation: Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., Japan. ryosuke.nakano@jp.astellas.com
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Nakano
authors.forename: Eiji
authors.initials: E
authors.lastname: Kurosaki
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Shimaya
authors.forename: Satoru
authors.initials: S
authors.lastname: Kajikawa
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shibasaki
mesh_terms: D000118:Acetylglucosaminidase / Q000652:urine; D000419:Albuminuria / Q000652:urine; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D001806:Blood Urea Nitrogen; D001835:Body Weight / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000652:urine; D003928:Diabetic Nephropathies / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007677:Kidney Function Tests; D008297:Male; D009765:Obesity / Q000097:blood / Q000150:complications / Q000652:urine; D009929:Organ Size / Q000187:drug effects; D010069:Oxadiazoles / Q000494:pharmacology*; D051381:Rats; D011924:Rats, Zucker; D014280:Triglycerides / Q000097:blood*
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D010069:Oxadiazoles; D014280:Triglycerides; C406084:YM 440; D002784:Cholesterol; D000118:Acetylglucosaminidase