VASCULAR BIOLOGY - HEMODYNAMICS - HYPERTENSION Hyperhomocysteinemia activates NF-κB and inducible nitric oxide synthase in the kidney

Zhang, Fan; Siow, Yaw L.; O, Karmin
April 2004
Kidney International;Apr2004, Vol. 65 Issue 4, p1327
Academic Journal
Hyperhomocysteinemia activates NF-κB and inducible nitric oxide synthase in the kidney. 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-κB), 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-κB 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-κB was determined by electrophoretic mobility shift assay. Role of inhibitor protein IκBα was examined by Western immunoblotting analysis. Results. There was a significant increase in the level of phosphorylated IκBα protein in kidneys of hyperhomocysteinemic rats. This resulted in a decrease in the IκBα protein level leading to NF-κB 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-κB inhibitor not only abolished NF-κB activation, but also reversed hyperhomocysteinemia-induced iNOS expression in the kidney. Conclusion. Hyperhomocysteinemia alone can activate NF-κB 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.


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