期刊
NEPHROLOGY DIALYSIS TRANSPLANTATION
卷 18, 期 2, 页码 265-272出版社
OXFORD UNIV PRESS
DOI: 10.1093/ndt/18.2.265
关键词
diabetic nephropathy; HMG-CoA reductase inhibitor; ICAM-1; macrophage; NF-kappa B; oxidative stress
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 mum(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. Conclusion. 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.
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