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Anti‐inflammatory effects of tetrahydrobiopterin on early rejection in renal allografts: modulation of inducible nitric oxide synthase
Author(s) -
Huisman Albert,
Vos Ingrid,
Faassen Ernst E.,
Joles Jaap A.,
Gröne HermannJosef,
Martasek Pavel,
Zonneveld AntonJan,
Vanin Anatoly F.,
Rabelink Ton J.
Publication year - 2002
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/fj.01-0890fje
Subject(s) - tetrahydrobiopterin , superoxide , nitric oxide , nitric oxide synthase , chemistry , biopterin , medicine , endocrinology , transplantation , kidney , monocyte , biochemistry , enzyme
Oxidative stress contributes to the development of early transplant failure. As nitric oxide synthases (NOS) can act as sources of superoxide, we investigated the effect of the NOS cofactor tetrahydrobiopterin (BH4) on oxyradical production and early rejection in a rat kidney transplantation model. Allograft transplantation (Brown Norway to Lewis) showed more renal superoxide production and monocyte infiltration when compared with isografts (Lewis to Lewis). Administration of the stable BH4 precursor sepiapterin had no effect on superoxide production in the isografts (51±10 vs. 69±17 cps/10 mg protein), but led to a marked decrease in superoxide production in the allografts (116±11 vs. 60±6 cps/10 mg protein; P <0.05) and was accompanied by a reduction in periarterial macrophage infiltration (3.3±0.7 vs. 1.3±0.3 cells/vessel; P <0.05) and an increase in NO production (78±22 vs. 173±12 AU/g kidney) ( P <0.01). In vitro experiments confirm that iNOS can produce superoxide mainly from the heme domain, whereas BH4 administration can reverse this superoxide production in the presence of adequate anti‐oxidant defense. Our findings support the hypothesis that BH4 can be used to modulate the function of the inflammatory iNOS isoform and suggest a potential therapeutic role for sepiapterin in early allograft rejection.