HMG-CoA reductase inhibitor ameliorates diabetic nephropathy by its pleiotropic effects in rats.
BACKGROUND
An inflammatory process may be one of the critical factors that contribute to the development of diabetic nephropathy (DN). We reported previously that intercellular adhesion molecule-1 (ICAM-1) is up-regulated and promotes macrophage infiltration in the glomeruli of diabetic rats. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have recently been emphasized to have anti-inflammatory effects; inhibition of leukocyte adhesion and migration, independent of the cholesterol-lowering effect. The present study was designed to test the hypothesis that statins prevent the development of DN by pleiotropic effects.


METHODS
Streptozotocin-induced diabetic rats were treated with cerivastatin (0.5 mg/kg body weight) or vehicle for 4 weeks. We analysed glomerular macrophage infiltration and ICAM-1 expression. We also evaluated major regulators of ICAM-1, activation of nuclear factor-kappa B (NF-kappaB) using electrophoretic mobility shift assay, and oxidative stress.


RESULTS
Statin treatment reduced urinary albumin excretion (UAE) (2.96+/-0.18 vs 2.38+/-0.06; log(10) UAE, P<0.05), glomerular size (12 150+/-329 vs 9963+/-307 micro m(2), P<0.05), and lowered blood pressure, compared with untreated diabetic rats. Immunohistochemistry revealed that macrophage infiltration and ICAM-1 expression in glomeruli were increased in diabetic rats and were inhibited by statin treatment. Renal NF-kappaB activity, urinary excretion and renal deposition of 8-OHdG were increased in diabetic rats, and reduced by statin treatment.


CONCLUSIONS
Statin treatment prevented glomerular injury, independent of the cholesterol-lowering effects. Our findings suggest that the beneficial effect might be mediated by pleiotropic effects including an anti-inflammatory action through a reduction of oxidative stress, NF-kappaB activation, ICAM-1 expression and macrophage infiltration in the early phase of DN.
Usui
Hitomi
H
Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Shikata
Kenichi
K
Matsuda
Mitsuhiro
M
Okada
Shinichi
S
Ogawa
Daisuke
D
Yamashita
Tetsuji
T
Hida
Kazuyuki
K
Satoh
Minoru
M
Wada
Jun
J
Makino
Hirofumi
H
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000652:urine; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003928:Diabetic Nephropathies / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000502:physiology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D000893:Anti-Inflammatory Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016328:NF-kappa B; D011725:Pyridines; D018799:Intercellular Adhesion Molecule-1; D000080242:8-Hydroxy-2'-Deoxyguanosine; C086276:cerivastatin; D003849:Deoxyguanosine