Anti-inflammatory effects of tetrahydrobiopterin on early rejection in renal allografts: modulation of inducible nitric oxide synthase.
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.
Huisman
Albert
A
Department of Vascular Medicine, University Medical Center, Utrecht, The Netherlands.
Vos
Ingrid
I
van Faassen
Ernst E
EE
Joles
Jaap A
JA
Gröne
Hermann-Josef
HJ
Martasek
Pavel
P
van Zonneveld
Anton-Jan
AJ
Vanin
Anatoly F
AF
Rabelink
Ton J
TJ
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D002465:Cell Movement; D006084:Graft Rejection / Q000188:drug therapy / Q000201:enzymology*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D016030:Kidney Transplantation; D007700:Kinetics; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D008954:Models, Biological; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D011621:Pteridines / Q000494:pharmacology; D011622:Pterins; D051381:Rats; D011917:Rats, Inbred Lew; D013481:Superoxides / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D011621:Pteridines; D011622:Pterins; D013481:Superoxides; D001708:Biopterins; D009569:Nitric Oxide; C016727:sepiapterin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C003402:sapropterin