Cyclosporin A Disrupts Bradykinin Signaling Through Superoxide

DOI Web Site 2 Citations
  • Michael Vetter
    From the Department of Medicine, Division of Hypertension, Case Western Reserve University (M.V., Z.-J.C., D.C., S.L., C.-H.C.), Cleveland, Ohio; the Department of Medicine, Reproductive Research Center, Shandong Provincial Hospital, Shandong University (Z.-J.C.), Jinan, Peoples Republic of China; and the Graduate Institute of Biological Sciences, National Taiwan University (G.-D.C.), Taipei, Taiwan.
  • Zi-Jiang Chen
    From the Department of Medicine, Division of Hypertension, Case Western Reserve University (M.V., Z.-J.C., D.C., S.L., C.-H.C.), Cleveland, Ohio; the Department of Medicine, Reproductive Research Center, Shandong Provincial Hospital, Shandong University (Z.-J.C.), Jinan, Peoples Republic of China; and the Graduate Institute of Biological Sciences, National Taiwan University (G.-D.C.), Taipei, Taiwan.
  • Geen-Dong Chang
    From the Department of Medicine, Division of Hypertension, Case Western Reserve University (M.V., Z.-J.C., D.C., S.L., C.-H.C.), Cleveland, Ohio; the Department of Medicine, Reproductive Research Center, Shandong Provincial Hospital, Shandong University (Z.-J.C.), Jinan, Peoples Republic of China; and the Graduate Institute of Biological Sciences, National Taiwan University (G.-D.C.), Taipei, Taiwan.
  • Danian Che
    From the Department of Medicine, Division of Hypertension, Case Western Reserve University (M.V., Z.-J.C., D.C., S.L., C.-H.C.), Cleveland, Ohio; the Department of Medicine, Reproductive Research Center, Shandong Provincial Hospital, Shandong University (Z.-J.C.), Jinan, Peoples Republic of China; and the Graduate Institute of Biological Sciences, National Taiwan University (G.-D.C.), Taipei, Taiwan.
  • Shiguo Liu
    From the Department of Medicine, Division of Hypertension, Case Western Reserve University (M.V., Z.-J.C., D.C., S.L., C.-H.C.), Cleveland, Ohio; the Department of Medicine, Reproductive Research Center, Shandong Provincial Hospital, Shandong University (Z.-J.C.), Jinan, Peoples Republic of China; and the Graduate Institute of Biological Sciences, National Taiwan University (G.-D.C.), Taipei, Taiwan.
  • Chung-Ho Chang
    From the Department of Medicine, Division of Hypertension, Case Western Reserve University (M.V., Z.-J.C., D.C., S.L., C.-H.C.), Cleveland, Ohio; the Department of Medicine, Reproductive Research Center, Shandong Provincial Hospital, Shandong University (Z.-J.C.), Jinan, Peoples Republic of China; and the Graduate Institute of Biological Sciences, National Taiwan University (G.-D.C.), Taipei, Taiwan.

Abstract

<jats:p> Cyclosporin A (CsA) is used to reduce transplant rejection rates. Chronic use, however, has a destructive toxic effect on the kidney, resulting in hypertension. In this study, we investigated the effects of CsA treatment on the bradykinin/soluble guanylate cyclase signaling cascade and the involvement of superoxide in LLC-PK1 porcine kidney proximal tubule cells. Treatment with 1 μmol/L CsA for 24 hours increased basal cGMP levels by 41%, whereas CsA inhibited bradykinin-stimulated cGMP production by 26%. Western blotting showed increased expression of eNOS, but no other protein in the bradykinin/soluble guanylate cyclase (sGC) pathway was affected. Using lucigenin-dependent chemiluminescence, we found that CsA treatment significantly increased superoxide production. Production of O <jats:sub>2</jats:sub> <jats:sup>−</jats:sup> was not significantly reduced by 10 μmol/L oxypurinol or 30 μmol/L ketoconazole. However, it was inhibited by the NADPH oxidase inhibitor diphenyleneiodonium chloride (10 μmol/L) as well as the O <jats:sub>2</jats:sub> <jats:sup>−</jats:sup> scavenger superoxide dismutase (SOD) (100 U). On treatment with 50 μmol/L quercetin, 10 mmol/L <jats:italic>N</jats:italic> -acetyl-cysteine, both antioxidants, as well as the O <jats:sub>2</jats:sub> <jats:sup>−</jats:sup> scavenger Tiron (10 mmol/L), concomitant with 1 μmol/L CsA for 24 hours the activation of cGMP production, was restored in combination with a reduction in O <jats:sub>2</jats:sub> <jats:sup>−</jats:sup> . Incubation with 100 μmol/L menadione, a reactive oxygen generator, and 10 nmol/L bradykinin showed similar effects on the level of cGMP as with CsA. CsA treatment was found to increase nitrotyrosine levels. These findings suggest that CsA activates a NADPH oxidase that releases O <jats:sub>2</jats:sub> <jats:sup>−</jats:sup> and disrupts the bradykinin/soluble guanylate cyclase pathway, probably by binding with NO to form peroxynitrite (ONOO <jats:sup>−</jats:sup> ). </jats:p>

Journal

  • Hypertension

    Hypertension 41 (5), 1136-1142, 2003-05

    Ovid Technologies (Wolters Kluwer Health)

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