Fluvastatin suppresses oxidative stress and fibrosis in the interstitium of mouse kidneys with unilateral ureteral obstruction

Kidney Int. 2001 Jun;59(6):2095-103. doi: 10.1046/j.1523-1755.2001.00724.x.

Abstract

Background: Recently, we demonstrated increased oxidative stress in the interstitium of ureteral obstructed kidneys based on the increased expression of heme oxygenase-1 and immunohistochemical detection of advanced glycation end products (AGE) in the interstitium. Antioxidant therapy may have a therapeutic potential toward interstitial fibrosis of unilateral ureteral obstruction (UUO) kidneys. Fluvastatin is an HMG-CoA reductase inhibitor and has been demonstrated to have an antioxidant activity in vitro.

Methods: The effects of fluvastatin on UUO kidneys from the viewpoints of antioxidant action in vivo and antifibrosis action were studied. To investigate the antioxidant action and its therapeutic efficacy of fluvastatin in UUO kidneys, AGE accumulation and fibrosis in the obstructed kidneys was compared among vehicle-, pravastatin-, or fluvastatin-treated (10 or 40 mg/kg/day) groups.

Results: Tubulointerstitial fibrosis was significantly attenuated in fluvastatin-treated animals. Fluvastatin significantly suppressed the degree of immunostaining of AGE in UUO kidneys.

Conclusions: These results provide evidence for the antioxidant action of fluvastatin in vivo. The decreased interstitial fibrosis along with a decreased oxidative stress marker in the interstitial lesion strongly suggests the existence of a causal relationship between them. Fluvastatin may have therapeutic value in slowing or preventing interstitial fibrosis in progressive renal disease.

MeSH terms

  • Actins / genetics
  • Animals
  • Cholesterol / blood
  • Disease Models, Animal
  • Fatty Acids, Monounsaturated / pharmacology*
  • Fibrosis
  • Fluvastatin
  • Gene Expression / drug effects
  • Glycation End Products, Advanced / analysis
  • Heme Oxygenase (Decyclizing) / genetics
  • Heme Oxygenase (Decyclizing) / metabolism
  • Heme Oxygenase-1
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Indoles / pharmacology*
  • Kidney / enzymology
  • Kidney / pathology
  • Membrane Proteins
  • Mice
  • Nephritis, Interstitial / drug therapy
  • Nephritis, Interstitial / metabolism
  • Nephritis, Interstitial / pathology
  • Oxidative Stress / drug effects*
  • Pravastatin / pharmacology
  • RNA, Messenger / analysis
  • Triglycerides / blood
  • Ureteral Obstruction / drug therapy*
  • Ureteral Obstruction / metabolism*
  • Ureteral Obstruction / pathology

Substances

  • Actins
  • Fatty Acids, Monounsaturated
  • Glycation End Products, Advanced
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Indoles
  • Membrane Proteins
  • RNA, Messenger
  • Triglycerides
  • Fluvastatin
  • Cholesterol
  • Heme Oxygenase (Decyclizing)
  • Heme Oxygenase-1
  • Hmox1 protein, mouse
  • Pravastatin