Nephrol Dial Transplant (2003) 18: 703-709
© 2003 European Renal Association-European Dialysis and Transplant Association
Lipid-lowering-independent effects of simvastatin on the kidney in experimental hypercholesterolaemia
1 Division of Hypertension and 2 Division of Cardiovascular Diseases, Department of Internal Medicine and 3 Department of Pediatrics, Mayo Clinic, Rochester, MN, USA, 4 National Cardiovascular Center Research Institute, Fujishirodai, Suita, Osaka, Japan, 5 Department of Medicine, University of Naples, Italy and 6 Department of Medicine-0682, University of California, San Diego, CA, USA
Background. Hypercholesterolaemia (HC), an independent risk factor for renal injury, is associated with formation of oxidized low-density-lipoprotein (ox-LDL), increased oxidative-stress and renal inflammation. HMG-CoA-reductase inhibitors are commonly used in HC, but their effects on renal haemodynamics and function in HC are poorly understood.
Methods. Pigs were studied after a 12-week normal diet, a 2% high-cholesterol diet (HC) or an HC diet supplemented with simvastatin (HC+simvastatin, 80 mg/day) (n=6–8 each group). Renal haemodynamics and function were quantified in vivo with electron-beam computed tomography (EBCT). Shock-frozen renal tissue was subsequently studied using immunohistochemistry.
Results. LDL cholesterol was similarly increased in HC and HC+simvastatin. Simvastatin-treated animals showed increased expression of endothelial nitric-oxide-synthase (eNOS), and decreased expression of the ox-LDL receptor LOX-1 in renal endothelial cells. Simvastatin also decreased tubular immunoreactivity of inducible-NOS, nitrotyrosine, nuclear-factor-
B, and tubuloglomerular trichrome staining. These were associated with a significant increase in cortical (6.1±0.1 vs 5.0±0.3 and 5.0±0.1 ml/min/cc, respectively, P<0.001) and medullary perfusion in HC+simvastatin compared to normal and HC.
Conclusions. Simvastatin attenuated the inflammatory and pro-oxidative environment as well as fibrosis in kidneys in pigs with diet-induced HC, in association with enhanced renal perfusion. These cholesterol-lowering-independent changes imply novel renoprotective effects of statins in the setting of HC and atherosclerosis.
Keywords: HMG-CoA reductase inhibitors; hypercholesterolaemia; kidney
Correspondence and offprint requests to: Lilach O. Lerman, MD, PhD, Division of Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Email: Lerman.lilach{at}mayo.edu
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