Pitavastatin ameliorates albuminuria and renal mesangial expansion by downregulating NOX4 in db/db mice

Kidney Int. 2007 Aug;72(4):473-80. doi: 10.1038/sj.ki.5002366. Epub 2007 Jun 13.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8-Hydroxy-2'-Deoxyguanosine
  • Albuminuria / etiology
  • Albuminuria / metabolism
  • Albuminuria / pathology
  • Albuminuria / prevention & control*
  • Animals
  • Blood Glucose / drug effects
  • Body Weight / drug effects
  • Cell Proliferation / drug effects
  • Deoxyguanosine / analogs & derivatives
  • Deoxyguanosine / urine
  • Diabetes Mellitus, Type 2 / complications*
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Diabetic Nephropathies / complications
  • Diabetic Nephropathies / etiology
  • Diabetic Nephropathies / metabolism
  • Diabetic Nephropathies / pathology
  • Diabetic Nephropathies / prevention & control*
  • Dinoprost / analogs & derivatives
  • Dinoprost / urine
  • Disease Models, Animal
  • Down-Regulation
  • Fibronectins / genetics
  • Fibronectins / metabolism
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
  • Lipids / blood
  • Male
  • Mesangial Cells / drug effects*
  • Mesangial Cells / enzymology
  • Mesangial Cells / metabolism
  • Mesangial Cells / pathology
  • Mice
  • NADPH Oxidase 4
  • NADPH Oxidases / genetics
  • NADPH Oxidases / metabolism*
  • Oxidative Stress / drug effects*
  • Quinolines / pharmacology*
  • Quinolines / therapeutic use
  • RNA, Messenger / metabolism
  • Time Factors
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism

Substances

  • Blood Glucose
  • Fibronectins
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Lipids
  • Quinolines
  • RNA, Messenger
  • Transforming Growth Factor beta1
  • 8-epi-prostaglandin F2alpha
  • 8-Hydroxy-2'-Deoxyguanosine
  • Dinoprost
  • NADPH Oxidase 4
  • NADPH Oxidases
  • Nox4 protein, mouse
  • Deoxyguanosine
  • pitavastatin