pitavastatin and Diabetic-Nephropathies

The effect of pitavastatin and pravastatin treatment on renal function was compared in type 2 diabetic patients with nephropathy in a randomized, controlled, open-label, parallel and multi-centre study. Type 2 diabetic patients with modest renal impairment (serum creatinine level <1.4 mg/dl) accompanied by albuminuria (30-600 mg/g creatinine) were randomly assigned to receive 2 mg of pitavastatin (n = 44) or 10 mg of pravastatin (n = 43) for 12 months. At 12 months, pitavastatin significantly reduced urinary albumin-to-creatinine ratio than pravastatin in subjects with macroalbuminuria (-67.2% vs. +14.5%, p = 0.0040), but not in subjects with microalbuminuria. There was no significant difference in the change in estimated glomerular filtration rate between the two groups. Pitavastatin is more effective than pravastatin for the reduction of albuminuria in type 2 diabetic patients with early stage of diabetic nephropathy.

Topics: Aged; Albuminuria; Biomarkers; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Glomerular Filtration Rate; Humans; Male; Pravastatin; Quinolines; Treatment Outcome

Liver-type fatty acid-binding protein (l-FABP) is expressed in renal proximal tubules and is reported to be a useful marker for progression of chronic glomerulonephritis. The aim of this study was to determine whether urinary l-FABP levels are altered at various stages of diabetic nephropathy and whether pitavastatin affects urinary l-FABP levels in early diabetic nephropathy.. Fifty-eight patients with type 2 diabetes (34 men and 24 women, median age 52 years) and 20 healthy, age-matched subjects (group E) were recruited for the study. The diabetic patients included 12 patients without nephropathy (group A), 20 patients with microalbuminuria (group B), 14 patients with macroalbuminuria and normal renal function (group C), and 12 patients with chronic renal failure but not undergoing hemodialysis (blood creatinine >1.2 mg/dl; mean 2.5 mg/dl, group D). Twenty group B patients were randomly assigned to receive 1 mg/day pitavastatin (10 patients, group B1) or placebo (10 patients, group B2). Treatment was continued for 12 months. Urinary l-FABP levels were measured by enzyme-linked immunosorbent assay. Urinary 8-hydroxydeoxyguanosine and serum free fatty acids (FFAs) were also measured in group B.. Urinary l-FABP levels in groups A-D were 6.2 +/- 4.6 microg/g creatinine, 19.6 +/- 13.5 microg/g creatinine, 26.8 +/- 20.4 microg/g creatinine, and 52.4 +/- 46.8 microg/g creatinine, respectively. Urinary l-FABP levels in groups B-D were significantly higher than those in healthy subjects (group E, 5.8 +/- 4.0 microg/g creatinine) (group B, P < 0.05; group C, P < 0.01; group D, P < 0.01). In group B1, urinary albumin excretion (UAE) and urinary l-FABP levels were decreased after pitavastatin treatment (UAE before, 110 +/- 74 microg/min; 6 months, 88 +/- 60 microg/min, P < 0.05; 12 months, 58 +/- 32 microg/min, P < 0.01; l-FABP before, 18.6 +/- 12.5 microg/g creatinine; 6 months, 12.2 +/- 8.8 microg/g creatinine, P < 0.05; 12 months, 8.8 +/- 6.4 microg/g creatinine, P < 0.01). In group B2, UAE and l-FABP levels showed little change during the experimental period. In group B1, urinary 8-hydroxydeoxyguanosine was decreased 12 months after pitavastatin treatment (before 32.5 +/- 19.5 ng/mg creatinine, after 18.8 +/- 14.5 ng/mg creatinine, P < 0.01), but in group B2, these showed little difference during the experimental period. In both groups B1 and B2, serum FFAs showed little difference during the experimental period.. Urinary l-FABP levels appear to be associated with the progression of diabetic nephropathy, and pitavastatin may be effective in ameliorating tubulointerstitial damage in early diabetic nephropathy.

Topics: Adult; Albuminuria; Biomarkers; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Enzyme Inhibitors; Fatty Acid-Binding Proteins; Female; Humans; Male; Middle Aged; Quinolines; Regression Analysis; Time Factors

Recent studies suggest a potential benefit of the lipid-lowering medication in the treatment of chronic kidney disease (CKD) such as diabetic nephropathy. Although statins have been widely used to lower serum cholesterol levels, the effect of these drugs on diabetic nephropathy has not been fully elucidated. In the present study, therefore, we addressed the role of different kinds of statins on diabetic nephropathy in db/db mice. Mice were fed with a standard diet with 0.005% (w/w) of pitavastatin, rosuvastatin, and pravastatin for 8 weeks starting from 8 weeks of age. The treatment with statins did not affect the food intake, body weight gain, adiposity, or blood pressure in db/db mice. Treatment with statins also had no effect on plasma lipid levels. In terms of the effect on albuminuria, pitavastatin and rosuvastatin reduced the urinary excretion of albumin by 60 and 40%, respectively, but not pravastatin, suggesting the effect of these two drugs on diabetic nephropathy. Furthermore, pitavastatin and rosuvastatin improved glomerular hypertrophy. All statins treatment improved insulin resistance. In addition, rosuvastatin and pravastatin treatment reduced oxidative stress measured by urinary 8-OHdG level, whereas the statins had no effect on the inflammatory response in the kidney of db/db mice. These results are not consistent with the renoprotective effect of statins. In conclusion, our data suggest that pitavastatin and rosuvastatin can improve diabetic nephropathy through the suppression of glomerular hypertrophy, independent of lipid-lowering or anti-oxidative effects.

Topics: Adiposity; Albuminuria; Animals; Blood Pressure; Body Weight; Creatinine; Diabetic Nephropathies; Fluorobenzenes; Insulin Resistance; Male; Mice; Oxidative Stress; Pravastatin; Pyrimidines; Quinolines; Real-Time Polymerase Chain Reaction; Rosuvastatin Calcium; Sulfonamides

1. The aim of the present study was to investigate whether or not pitavastatin ameliorates diabetic nephropathy and if inhibition of the rennin-angiotensin-aldosterone system (RAAS) is associated with any renoprotective effects. Pitavastatin (10mg/ kg/day) and/or spironolactone (100mg/kg/day) were given by gavage for 3weeks to uninephrectomized rats with streptozotocin-induced diabetes. 2. Pitavastatin or spironolactone significantly reduced proteinuria and collagen deposition, and normalized creatinine clearance, serum creatinine levels and blood urea nitrogen concentrations. 3. Reverse transcription polymerase chain reaction analysis showed that the renal expression of collagenI, transforming growth factor-β and monocyte chemoattractant-1 were increased in diabetic rats and reduced by the pitavastatin and/or spironolactone treatment. 4. These agents also decreased angiotensin converting enzyme expression and aldosterone concentrations in the renal homogenate, but had no effect on blood glucose, haemoglobinA(1c) , and plasma total cholesterol, Na(+) , K(+) , aldosterone and NOx levels, or on systolic blood pressure measured by the tail-cuff method. Interestingly, cotreatment with pitavastatin and spironolactone did not result in additional normalization. 5. These results suggest that pitavastatin shows renoprotective effects against diabetic nephropathy mediated in part by inhibition of the renal RAAS, including the suppression of angiotensin-converting enzyme expression and aldosterone production.

Topics: Aldosterone; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Kidney; Male; Peptidyl-Dipeptidase A; Quinolines; Rats; Rats, Wistar; Renin-Angiotensin System; Spironolactone

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.

Topics: Animals; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Glycated Hemoglobin; GTP Cyclohydrolase; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunohistochemistry; Mice; Mice, Inbred C57BL; NADPH Oxidases; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Protein Kinase C; Quinolines; RNA, Messenger; Tyrosine

Recent studies have uncovered various pleiotrophic effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase-inhibiting drugs (statins). Several studies have identified a beneficial effect of statins on diabetic nephropathy; however, the molecular mechanisms are unclear. In this study, we show that statin ameliorates nephropathy in db/db mice, a rodent model of type 2 diabetes, via downregulation of NAD(P)H oxidase NOX4, which is a major source of oxidative stress in the kidney. Pitavastatin treatment for 2 weeks starting at 12 weeks of age significantly reduced albuminuria in the db/db mice concomitant with a reduction of urinary 8-hydroxy-2'-deoxyguanosine and 8-epi-prostaglandin F(2alpha). Immunohistochemical analysis found increased amounts of 8-hydroxy-2'-deoxyguanosine and NOX4 protein in the kidney of db/db mice. Quantitative reverse transcription-polymerase chain reaction also showed increased levels of NOX4 mRNA. Pitavastatin normalized all of these changes in the kidneys of diabetic animals. Additionally, 12-week treatment with the statin completely normalized the levels of transforming growth factor-beta1 and fibronectin mRNA as well as the mesangial expansion characteristic of diabetic nephropathy. Our study demonstrates that pitavastatin ameliorates diabetic nephropathy in db/db mice by minimizing oxidative stress by downregulating NOX4 expression. These findings may provide insight into the mechanisms of statin therapy in early stages of diabetic nephropathy.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Albuminuria; Animals; Blood Glucose; Body Weight; Cell Proliferation; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dinoprost; Disease Models, Animal; Down-Regulation; Fibronectins; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipids; Male; Mesangial Cells; Mice; NADPH Oxidase 4; NADPH Oxidases; Oxidative Stress; Quinolines; RNA, Messenger; Time Factors; Transforming Growth Factor beta1