RESUMEN
BACKGROUND: Chronic kidney disease (CKD) results in accelerated atherosclerosis and cardiovascular disease. This is primarily mediated by oxidative stress, inflammation and dyslipidemia. By mediating reverse cholesterol transport and exerting antioxidant/anti-inflammatory actions, high-density lipoprotein (HDL) and ApoA-1 protect against atherosclerosis. Plasma Apo-1, HDL cholesterol and HDL antioxidant/anti-inflammatory activities are reduced in CKD. ApoA-1 mimetic peptides associate with and enhance antioxidant/anti-inflammatory properties of HDL. We hypothesized that long-term administration of ApoA-1 mimetic peptide, L4F, may ameliorate inflammation and oxidative stress in the conduit arteries in experimental CKD. METHODS: After 5/6 nephrectomy, rats were randomized to L4F (5 mg/kg s.c. 3 times weekly for 4 weeks) and placebo-treated groups. Sham-operated rats served as controls. RESULTS: The untreated CKD group exhibited marked lipid accumulation and upregulations of NAD(P)H oxidase subunits (gp91(phox), p22(phox), and p47(phox)), COX-2, 12-lipoxygenase, MCP-1, PAI-1, myeloperoxidase and iNOS, NFκB activation and nitrotyrosine accumulation in the thoracic aorta. L4F administration reversed or attenuated these abnormalities without altering renal function or plasma lipids. CONCLUSIONS: CKD leads to lipid accumulation and upregulation of pro-atherogenic pathways in the artery wall. These abnormalities are attenuated by ApoA-1 mimetic peptide, pointing to its protective effect in CKD. Future studies are needed to explore the effect of these peptides in CKD patients.
Asunto(s)
Aorta Torácica/metabolismo , Apolipoproteína A-I/farmacología , Arteritis/metabolismo , Aterosclerosis/metabolismo , Estrés Oxidativo/efectos de los fármacos , Péptidos/farmacología , Insuficiencia Renal Crónica/metabolismo , Regulación hacia Arriba , Uremia/metabolismo , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Apolipoproteína A-I/fisiología , Araquidonato 12-Lipooxigenasa/metabolismo , Arteritis/prevención & control , Aterosclerosis/prevención & control , Quimiocina CCL2/metabolismo , Ciclooxigenasa 2/metabolismo , Masculino , NADPH Oxidasas/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Peroxidasa/metabolismo , Inhibidor 1 de Activador Plasminogénico/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Ratas , Ratas Sprague-Dawley , Insuficiencia Renal Crónica/fisiopatología , Tirosina/análogos & derivados , Tirosina/metabolismo , Quinasa de Factor Nuclear kappa BRESUMEN
BACKGROUND: Chronic renal failure (CRF) causes oxidative stress, inflammation, oxidation of lipoproteins, impaired maturation of HDL and accelerated atherosclerosis. Uptake of oxidized lipoproteins by macrophages via scavenger receptors (scavenger receptor class A type I--SR-AI, and lectin-like oxidized LDL receptor--LOX-1) leads to foam cell formation and atherosclerosis. HDL mitigates atherosclerosis by retrieving surplus cholesterol via ATP binding cassette transporter A1 (ABCA1) and ABCG1 transporters whose expression is regulated by liver X receptor (LXR). Free cholesterol reaching the surface of HDL is esterified by lecithin-cholesterol acyltransferase (LCAT) and sequestered in the core of HDL, thereby maximizing cholesterol uptake. In the liver, lipid-rich HDL unloads its lipid contents via reversible binding to SR-BI while lipid-poor HDL is degraded by the holo-receptor (ATP synthase beta-chain). METHODS: Expression of the above molecules involved in reverse cholesterol/lipid transport was assessed in rats 8 weeks after 5/6 nephrectomy (CRF) or sham operation. RESULTS: CRF caused heavy accumulation of neutral lipids, upregulation of SR-AI, LOX-1, LXRalpha/beta, ABCA1 and ABCG1 in the aorta, reduction in LCAT in the plasma and no significant change in either SR-BI or beta-chain ATP synthase in the liver. CONCLUSIONS: Lipid accumulation despite upregulation of the efflux (LXR, ABCA1, ABCG1) system in the aorta in CRF is largely due to upregulation of influx (SR-AI and LOX-1) pathway and LCAT deficiency.
Asunto(s)
Colesterol/metabolismo , Regulación de la Expresión Génica , Fallo Renal Crónico/sangre , Animales , Inflamación , Lípidos/química , Hígado/metabolismo , Macrófagos/metabolismo , Masculino , Modelos Biológicos , Nefrectomía , Estrés Oxidativo , Ratas , Ratas Sprague-Dawley , Receptores Depuradores/metabolismoRESUMEN
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.