Abstract
Objective : It is generally considered that HMG-CoA reductase inhibitors (statins) have renoprotective effects via a pathway independent of their cholesterol lowering cascade. In the kidneys of diabetic nephropathy patients, monomeric endothelial nitric oxide synthase (eNOS) is thought to be over-expressed and its dimerization suppressed. In the present study, we investigated the expression of eNOS and oxidative stress in type 2 diabetic KK-Ay/Ta mice treated with pitavastatin, one of the statins.
Materials : Male diabetic KK-Ay/Ta Jcl mice (8 weeks of age).
Methods : KK-Ay/Ta mice were divided into 3 groups as follows : pitavastatin 3mg/kg/day (n=5) and 10mg/kg/day (n=5) groups and a control group (n=5). They were given pitavastatin intraperitoneally for 8 weeks starting at 8 weeks of age. The urinary albumin/creatinine ratio (ACR), urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG), body weight, fasting blood glucose, blood HbAlc, serum total cholesterol and triglyceride were measured. The intraperitoneal glucose tolerance test (IPGTT) was performed to evaluate impaired glucose tolerance. Then eNOS, nitrotyrosine and p47 phox protein expressions in the kidneys were evaluated by immunohistochemical analyses and/or Western blot analyses. Guanosine triphosphate cyclohydrolase 1 (GTPCH-1) mRNA expression in the kidneys was evaluated using a real-time PCR assay.
Results : Pitavastatin improved the levels of urinary ACR and 8-OHdG, blood HbAlc and IPGTT. Protein levels of eNOS, nitrotyrosine and p47 phox in the kidneys were decreased in the pitavastatin-treated groups compared with those in the non-treated control group. GTPCH-1 mRNA expression was significantly increased in the pitavastatin groups. There were no significant changes in body weight or levels of fasting blood glucose, serum total cholesterol and serum triglyceride among all groups.
Conclusion : Pitavastatin improved urinary ACR apparently due to suppression of eNOS expression and its anti-oxidant effect in the kidneys of KK-Ay/Ta mice.
