Nitration and inactivation of manganese superoxide dismutase in chronic rejection of human renal allografts

Academic Article

Abstract

  • Inflammatory processes in chronic rejection remain a serious clinical problem in organ transplantation. Activated cellular infiltrate produces high levels of both superoxide and nitric oxide. These reactive oxygen species interact to form peroxynitrite, a potent oxidant that can modify proteins to form 3-nitrotyrosine. We identified enhanced immunostaining for nitrotyrosine localized to tubular epithelium of chronically rejected human renal allografts. Western blot analysis of rejected tissue demonstrated that tyrosine nitration was restricted to a few specific polypeptides. Immunoprecipitation and amino acid sequencing techniques identified manganese superoxide dismutase, the major anti-oxidant enzyme in mitochondria, as one of the targets of tyrosine nitration. Total manganese superoxide dismutase protein was increased in rejected kidney, particularly in the tubular epithelium; however, enzymatic activity was significantly decreased. Exposure of recombinant human manganese superoxide dismutase to peroxynitrite resulted in a dose-dependent (IC50 = 10 μM) decrease in enzymatic activity and concomitant increase in tyrosine nitration. Collectively, these observations suggest a rule for peroxynitrite during development and progression of chronic rejection in human renal allografts. In addition, inactivation of manganese superoxide dismutase by peroxynitrite may represent a general mechanism that progressively increases the production of peroxynitrite, leading to irreversible oxidative injury to mitochondria.
  • Authors

    Digital Object Identifier (doi)

    Author List

  • Macmillan-Crow LA; Crow JP; Kerby JD; Beckman JS; Thompson JA
  • Start Page

  • 11853
  • End Page

  • 11858
  • Volume

  • 93
  • Issue

  • 21