title: Hyperhomocysteinemia activates NF-kappaB and inducible nitric oxide synthase in the kidney.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Hong Kong, Hong Kong, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: Yaw L
authors.initials: YL
authors.lastname: Siow
authors.forename: Karmin
authors.initials: K
authors.lastname: O
mesh_terms: D000818:Animals; D004032:Diet; D020138:Hyperhomocysteinemia / Q000201:enzymology / Q000378:metabolism*; D007668:Kidney / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008715:Methionine / Q000008:administration & dosage; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013859:Thiocarbamates / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000096:biosynthesis
chemical_list: D016328:NF-kappa B; D012333:RNA, Messenger; D013859:Thiocarbamates; C066229:prolinedithiocarbamate; C002744:3-nitrotyrosine; D014443:Tyrosine; D011392:Proline; D008715:Methionine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat