Hyperhomocysteinemia activates NF-κB and inducible nitric oxide synthase in the kidney

被引:31
|
作者
Zhang, F
Siow, YL
O, K
机构
[1] Univ Manitoba, St Boniface Gen Hosp Res Ctr,Dept Anim Sci, Integrat Biol Lab, Natl Ctr Agrifood Res Med, Winnipeg, MB R2H 2A6, Canada
[2] Univ Hong Kong, Fac Med, Dept Pharmacol, Hong Kong, Hong Kong, Peoples R China
[3] Univ Manitoba, St Boniface Gen Hosp Res Ctr,Dept Physiol, Integrat Biol Lab, Natl Ctr Agrifood Res Med, Winnipeg, MB R2H 2A6, Canada
关键词
homocysteine; nuclear factor-kappa B; inducible nitric oxide synthase; peroxynitrite;
D O I
10.1111/j.1523-1755.2004.00510.x
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Background. Hyperhomocysteinemia is an independent risk factor for cardiovascular disorders. Injury of multiple organs, including the kidney, was observed in hyperhomocysteinemic individuals. Activation of a transcription factor, namely, nuclear factor kappa B (NF-kappaB), plays an important role in inflammatory response and can exacerbate organ injury. The objective of the present study was to investigate the effect of hyperhomocysteinemia on renal NF-kappaB activation and the consequence of such activation. Methods. Hyperhomocysteinemia was induced in Sprague-Dawley rats after 4 weeks of a high-methionine diet. Activation of NF-kappaB was determined by electrophoretic mobility shift assay. Role of inhibitor protein IkappaBalpha was examined by Western immunoblotting analysis. Results. There was a significant increase in the level of phosphorylated IkappaBalpha protein in kidneys of hyperhomocysteinemic rats. This resulted in a decrease in the IkappaBalpha protein level leading to NF-kappaB activation. As a consequence, the expression of inducible nitric oxide synthase (iNOS) mRNA and protein was significantly elevated in kidneys of hyperhomocysteinemic rats. Increased nitric oxide production (150% of the control) resulted in peroxynitrite formation in these kidneys. Pretreatment of rats with a NF-kappaB inhibitor not only abolished NF-kappaB activation, but also reversed hyperhomocysteinemia-induced iNOS expression in the kidney. Conclusion. Hyperhomocysteinemia alone can activate NF-kappaB and hence induce iNOS-mediated nitric oxide production in the kidney leading to increased peroxynitrite formation. This may represent one of the mechanisms for renal dysfunction in hyperhomocysteinemia.
引用
收藏
页码:1327 / 1338
页数:12
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