Increased tyrosine nitration of the brain in chronic renal insufficiency: Reversal by antioxidant therapy and angiotensin-converting enzyme inhibition

Interaction of reactive oxygen species with nitric oxide promotes nitric ox ide 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 ani mals with various degenerative, ischemic, toxic, and other neurologic disor ders. According to earlier studies, reactive oxygen species activity is inc reased and neuronal NO synthase expression in the brain is elevated in anim als with chronic renal failure (CRF). It was hypothesized, therefore, that tyrosine nitration must be increased in the uremic brain. This hypothesis w as tested, through determination of nitrotyrosine abundance (by Western blo t 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 cap topril-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 termi nals of the cortical neurons. Both antioxidant therapy and captopril admini stration alleviated oxidative stress (as evidenced by normalization of plas ma lipid peroxidation product malondialdehyde) and significantly reduced ni trotyrosine abundance in the cerebral cortex of the treated CRF group. In c onclusion, CRF resulted in oxidative stress and increased tyrosine nitratio n in the cerebral cortex. Antioxidant therapy and angiotensin-converting en zyme inhibition alleviated the CRF-induced oxidative stress and mitigated t yrosine nitration in the rats with CRF.