Eplerenone Shows Renoprotective Effect by Reducing LOX-1–Mediated Adhesion Molecule, PKCε-MAPK-p90RSK, and Rho-Kinase Pathway

DOI Web Site 17 Citations
  • Naohiko Kobayashi
    From the Department of Hypertension and Cardiorenal Medicine (N.K., K.H., T.H., K.Y., S.M., S.N., Y.T., H.M.), Dokkyo University School of Medicine, Tochigi, Japan; and the Division of Nephrology and Endocrinology (A.T., M.L.O.), University of Tokyo, Tokyo, Japan.
  • Kazuyoshi Hara
    From the Department of Hypertension and Cardiorenal Medicine (N.K., K.H., T.H., K.Y., S.M., S.N., Y.T., H.M.), Dokkyo University School of Medicine, Tochigi, Japan; and the Division of Nephrology and Endocrinology (A.T., M.L.O.), University of Tokyo, Tokyo, Japan.
  • Akihiro Tojo
    From the Department of Hypertension and Cardiorenal Medicine (N.K., K.H., T.H., K.Y., S.M., S.N., Y.T., H.M.), Dokkyo University School of Medicine, Tochigi, Japan; and the Division of Nephrology and Endocrinology (A.T., M.L.O.), University of Tokyo, Tokyo, Japan.
  • Maristela Lika Onozato
    From the Department of Hypertension and Cardiorenal Medicine (N.K., K.H., T.H., K.Y., S.M., S.N., Y.T., H.M.), Dokkyo University School of Medicine, Tochigi, Japan; and the Division of Nephrology and Endocrinology (A.T., M.L.O.), University of Tokyo, Tokyo, Japan.
  • Takeaki Honda
    From the Department of Hypertension and Cardiorenal Medicine (N.K., K.H., T.H., K.Y., S.M., S.N., Y.T., H.M.), Dokkyo University School of Medicine, Tochigi, Japan; and the Division of Nephrology and Endocrinology (A.T., M.L.O.), University of Tokyo, Tokyo, Japan.
  • Kohtaro Yoshida
    From the Department of Hypertension and Cardiorenal Medicine (N.K., K.H., T.H., K.Y., S.M., S.N., Y.T., H.M.), Dokkyo University School of Medicine, Tochigi, Japan; and the Division of Nephrology and Endocrinology (A.T., M.L.O.), University of Tokyo, Tokyo, Japan.
  • Shin-ichiro Mita
    From the Department of Hypertension and Cardiorenal Medicine (N.K., K.H., T.H., K.Y., S.M., S.N., Y.T., H.M.), Dokkyo University School of Medicine, Tochigi, Japan; and the Division of Nephrology and Endocrinology (A.T., M.L.O.), University of Tokyo, Tokyo, Japan.
  • Shigefumi Nakano
    From the Department of Hypertension and Cardiorenal Medicine (N.K., K.H., T.H., K.Y., S.M., S.N., Y.T., H.M.), Dokkyo University School of Medicine, Tochigi, Japan; and the Division of Nephrology and Endocrinology (A.T., M.L.O.), University of Tokyo, Tokyo, Japan.
  • Yusuke Tsubokou
    From the Department of Hypertension and Cardiorenal Medicine (N.K., K.H., T.H., K.Y., S.M., S.N., Y.T., H.M.), Dokkyo University School of Medicine, Tochigi, Japan; and the Division of Nephrology and Endocrinology (A.T., M.L.O.), University of Tokyo, Tokyo, Japan.
  • Hiroaki Matsuoka
    From the Department of Hypertension and Cardiorenal Medicine (N.K., K.H., T.H., K.Y., S.M., S.N., Y.T., H.M.), Dokkyo University School of Medicine, Tochigi, Japan; and the Division of Nephrology and Endocrinology (A.T., M.L.O.), University of Tokyo, Tokyo, Japan.

Abstract

<jats:p> Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) may play an important role in atherosclerosis by inducing leukocyte adhesion molecules, such as intercellular and vascular cell adhesion molecule-1 (intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1]). We hypothesized that eplerenone, a novel selective aldosterone blocker, produces inhibition of LOX-1–mediated adhesion molecules, suppresses mitogen-activated protein (MAP) kinase and its downstream effector p90 ribosomal S6 kinase (p90RSK) through the protein kinase Cε (PKCε) pathway, and improves endothelial function by inhibition of Rho-kinase in the renal cortex of Dahl salt-sensitive hypertensive (DS) and salt-resistant (DR) rats. Eplerenone (10, 30, and 100 mg/kg per day) was given from the age of 6 weeks to the left ventricular hypertrophy stage (11 weeks) for 5 weeks. At 11 weeks, expression levels of LOX-1, ICAM-1, VCAM-1, and Rho-kinase were higher in DS rats than in DR rats and were decreased by eplerenone. Similarly, upregulated phosphorylation of PKCε, MAP kinase, and p90RSK in DS rats was also inhibited by eplerenone. In contrast, downregulated endothelial nitric oxide synthase mRNA was increased by eplerenone to a similar degree as after treatment with Y-27632, a selective Rho-kinase inhibitor. Eplerenone administration resulted in significant improvement in glomerulosclerosis (eplerenone 10 mg, −61%; 30 mg, −78%; and 100 mg, −84% versus DS; <jats:italic>P</jats:italic> <0.01, respectively) and urinary protein (10 mg, −78%; 30 mg, −87%; and 100 mg, −88% versus DS; <jats:italic>P</jats:italic> <0.01, respectively). These results suggest that the renoprotective effects of eplerenone may be partly caused by inhibition of LOX-1–mediated adhesion molecules and PKCε–MAP kinase–p90RSK pathway, and improvement in endothelial function. </jats:p>

Journal

  • Hypertension

    Hypertension 45 (4), 538-544, 2005-04

    Ovid Technologies (Wolters Kluwer Health)

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