Increased Tyrosine Nitration of the Brain in Chronic Renal Insufficiency: Reversal by Antioxidant Therapy and Angiotensin-Converting Enzyme Inhibition

Abstract

Abstract. Interaction of reactive oxygen species with nitric oxide promotes nitric oxide inactivation and generation of cytotoxic reactive nitrogen species that attack DNA, lipids, and proteins. Nitration of free tyrosine and tyrosine residues of proteins results in production of nitrotyrosine, which can lead to excitotoxicity and frequently is found in the brain of patients and animals with various degenerative, ischemic, toxic, and other neurologic disorders. According to earlier studies, reactive oxygen species activity is increased and neuronal NO synthase expression in the brain is elevated in animals with chronic renal failure (CRF). It was hypothesized, therefore, that tyrosine nitration must be increased in the uremic brain. This hypothesis was tested, through determination of nitrotyrosine abundance (by Western blot analysis), as well as distribution (by immunohistology), in the cerebrum of rats with CRF 6 wk after 5/6 nephrectomy. The results were compared with those of sham-operated controls and antioxidant (lazaroid)-treated and captopril-treated rats with CRF. Western blot analysis revealed a significant increase in nitrotyrosine abundance in the cerebral cortex of rats with CRF. This was accompanied by an intense nitrotyrosine staining of the neuronal processes, including proximal segments of dendrites, axons, and axon terminals of the cortical neurons. Both antioxidant therapy and captopril administration alleviated oxidative stress (as evidenced by normalization of plasma lipid peroxidation product malondialdehyde) and significantly reduced nitrotyrosine abundance in the cerebral cortex of the treated CRF group. In conclusion, CRF resulted in oxidative stress and increased tyrosine nitration in the cerebral cortex. Antioxidant therapy and angiotensin-converting enzyme inhibition alleviated the CRF-induced oxidative stress and mitigated tyrosine nitration in the rats with CRF.