title: Effect of pitavastatin on type 2 diabetes mellitus nephropathy in KK-Ay/Ta mice.
abstract: It is generally considered that 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) have renoprotective effects via a pathway independent of their cholesterol-lowering cascade. In the kidneys of diabetic nephropathy, monomeric endothelial nitric oxide synthase (eNOS) is thought to be overexpressed; and its dimerization is suppressed. In the present study, we investigated the expression of eNOS and oxidative stress in type 2 diabetes mellitus KK-Ay/Ta mice treated with pitavastatin, one of the statins. The KK-Ay/Ta mice were divided into 3 groups and given pitavastatin intraperitoneally starting at 8 weeks of age for 8 weeks: pitavastatin 3 mg/(kg d) (n=5), pitavastatin 10 mg/(kg d) (n=5), and a control group (n=10). The urinary albumin-creatinine ratio (ACR), urinary 8-hydroxy-2'-deoxyguanosine, body weight, fasting blood glucose, hemoglobin A1c, total cholesterol, and triglyceride were measured; and the intraperitoneal glucose tolerance test was performed. The eNOS, nitrotyrosine, and p47 phox were evaluated by immunohistochemical analyses and/or Western blot analyses. Guanosine triphosphate cyclohydrolase 1 messenger RNA expression in the kidneys was evaluated using a real-time polymerase chain reaction assay. Pitavastatin improved the levels of urinary ACR and 8-hydroxy-2'-deoxyguanosine, intraperitoneal glucose tolerance test, and hemoglobin A1c. Protein levels of monomeric eNOS, nitrotyrosine, and p47 phox in the kidneys were decreased in the pitavastatin-treated groups. Guanosine triphosphate cyclohydrolase 1 messenger RNA expression was significantly increased in the pitavastatin groups. There were no significant changes in body weight, levels of fasting blood glucose, serum total cholesterol, triglyceride, and blood pressure among all groups. Pitavastatin improved urinary ACR apparently because of suppression of eNOS uncoupling and its antioxidant effect in the kidneys of KK-Ay/Ta mice.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Tanimoto
authors.forename: Tomohito
authors.initials: T
authors.lastname: Gohda
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Aoki
authors.forename: Maki
authors.initials: M
authors.lastname: Murakoshi
authors.forename: Kaori
authors.initials: K
authors.lastname: Yamada
authors.forename: Takahiko
authors.initials: T
authors.lastname: Yamazaki
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kaneko
authors.forename: Satoshi
authors.initials: S
authors.lastname: Horikoshi
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tomino
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy*; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D006136:GTP Cyclohydrolase / Q000235:genetics; D006442:Glycated Hemoglobin / Q000032:analysis; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000032:analysis; D052247:Nitric Oxide Synthase Type II / Q000032:analysis; D052250:Nitric Oxide Synthase Type III; D011493:Protein Kinase C / Q000502:physiology; D011804:Quinolines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis
chemical_list: D006136:GTP Cyclohydrolase; D006442:Glycated Hemoglobin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019255:NADPH Oxidases; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D011493:Protein Kinase C; D011804:Quinolines; D012333:RNA, Messenger; D014443:Tyrosine; C002744:3-nitrotyrosine; C496315:Nos3 protein, mouse; C060505:neutrophil cytosolic factor 1; C108475:pitavastatin