Journal Article

HMG‐CoA reductase inhibitor ameliorates diabetic nephropathy by its pleiotropic effects in rats

Hitomi Usui, Kenichi Shikata, Mitsuhiro Matsuda, Shinichi Okada, Daisuke Ogawa, Tetsuji Yamashita, Kazuyuki Hida, Minoru Satoh, Jun Wada and Hirofumi Makino

in Nephrology Dialysis Transplantation

Published on behalf of European Renal Association - European Dialysis and Transplant Assoc

Volume 18, issue 2, pages 265-272
Published in print February 2003 | ISSN: 0931-0509
Published online February 2003 | e-ISSN: 1460-2385 | DOI: http://dx.doi.org/10.1093/ndt/18.2.265
HMG‐CoA reductase inhibitor ameliorates diabetic nephropathy by its pleiotropic effects in rats

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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‐κB) 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; log10 UAE, P<0.05), glomerular size (12 150±329 vs 9963±307 µm2, 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‐κB 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‐κB activation, ICAM‐1 expression and macrophage infiltration in the early phase of DN.

Keywords: diabetic nephropathy; HMG‐CoA reductase inhibitor; ICAM‐1; macrophage; NF‐κB; oxidative stress

Journal Article.  3968 words.  Illustrated.

Subjects: Nephrology

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