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

M. Fujii, T. Inoguchi, Y. Maeda, S. Sasaki, F. Sawada, R. Saito, K. Kobayashi, H. Sumimoto, R. Takayanagi

Research output: Contribution to journalArticlepeer-review

80 Citations (Scopus)

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. 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-β1 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.

Original languageEnglish
Pages (from-to)473-480
Number of pages8
JournalKidney International
Volume72
Issue number4
DOIs
Publication statusPublished - Aug 2007

All Science Journal Classification (ASJC) codes

  • Nephrology

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