Anti‐inflammatory effects of tetrahydrobiopterin on early rejection in renal allografts: modulation of inducible nitric oxide synthase

Abstract

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.

CCR2-Mediated Antiinflammatory Effects of Endothelial Tetrahydrobiopterin Inhibit Vascular Injury-Induced Accelerated Atherosclerosis

“…23 Although several studies have now shown salutary effects of BH4 on endothelial function and eNOS regulation (reviewed in Alp et al 24 ), a potential role for BH4 in modulating vascular inflammation has been suggested by only one previous study, in a model of transplant rejection. 25 ROS have been implicated in initiating inflammatory responses through activation of signal transduction pathways such as mitogen-activated protein (MAP) kinases and phosphoinositide-3-kinases (PI-3-K) as well as redox-sensitive transcription factors, such as NF-⌲B and AP-1 leading to enhanced gene expression of proinflammatory mediators (reviewed in Kunsch et al 5 ). Among the multiple gene products regulated by these transcription factors involved in atherosclerosis is the CC-CK MCP-1.…”

Short-term antioxidant diet prevents hyperfiltration in young male rat kidney subjected to ischemia/reperfusion injury

“…Substantial elevations of NO can also contribute to formation of peroxynitrites and increased oxidative damage [23,24]. Although the urinary NO was higher in the REG diet males at 8 weeks compared to the AO diet males, this difference did not reach statistical significance, This may be due to the fact that urinary NO reflects the total circulating NO in addition to the renal NO.…”

“…NOS isoforms can act as sources of superoxide. All of these molecules can damage the mitochondria and cause cell death [23,24]. NO synthesized by eNOS plays an important role in maintaining renal blood flow following renal transplantation and therefore normal regulation of the NO system needs to be maintained [25].…”

The complex role of iNOS in acutely rejecting cardiac transplants

“…This consideration requires that more studies are necessary to better understand the post-translational modification of NO production from iNOS by tetrahydrobiopterin in transplant rejection. This concept is inferred from other recent findings in a renal transplant model in which supplementation with sepiapterin to increase levels of biopterin via the salvage pathway increased NO content and decreased superoxide production [149]. It was not clearly determined; however, that iNOS was the source of superoxide production in renal rejection and the improved NO production following treatment with sepiapterin occurred via iNOS or constitutive NOS.…”