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Calcineurin Alpha Inhibition Induces Nox2 Up‐regulation via NFκB
Author(s) -
Williams Clintoria,
Hoover Robert,
Gooch Jennifer
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.979.4
Subject(s) - calcineurin , nadph oxidase , nephrotoxicity , nfat , chemistry , pharmacology , western blot , reactive oxygen species , endocrinology , kidney , medicine , transplantation , biochemistry , gene
Although essential for preventing transplant rejection, prolonged calcineurin inhibitor (CNI) use induces nephrotoxicity. We showed that mice lacking the alpha catalytic isoform of calcineurin (CnAα) have a phenotype that mirrors CNI nephrotoxicity. Other studies implicate NADPH oxidase‐2 (Nox2) in the pathogenesis. This study seeks to determine if CnAα and Nox2 function in a common pathway. To determine the mechanism of CNI inhibition‐mediated increases in renal Nox2, WT mice were treated with cyclosporine A (CsA) for 6 weeks. In addition, Nox2 expression and activity were examined in CnAα ‐/‐ and CnAβ ‐/‐ mice and renal fibroblasts. In kidneys, co‐IP reveals that CsA treatment reduces CnAα association with its binding partner, calmodulin. Consistent with previous data, CnAβ and calmodulin association is not observed. Additionally, reduced CnAα activation is accompanied by increased Nox2 expression and ROS levels, as assessed by Western blot and Amplex Red. Consistently, renal Nox2 expression and ROS levels are increased in CnAα ‐/‐ mice but not CnAβ ‐/‐ . Surprisingly, NFAT transcriptional activity is unchanged in CnAα ‐/‐ mice compared to WT and CnAβ ‐/‐ , as assessed by luciferase activity. However, increased NFκB phosphorylation is observed. In CnAα ‐/‐ cells, NFκB inhibition with CAPE attenuates enhanced Nox2 expression and ROS levels. In conclusion, these data indicate that CsA‐induced CnAα inhibition and subsequent NFκB activation stimulates Nox2 up‐regulation. Therapeutic approaches using CNI that do not target CnAα could ameliorate oxidative damage associated with CNI nephrotoxicity. NIH‐T32 (CRW), NIH‐R01 (RSH), VA‐MERIT (JLG)