title: Reciprocal regulation between sirtuin-1 and angiotensin-II in the substantia nigra: implications for aging and neurodegeneration.
abstract: Local angiotensin II (AII) and sirtuin 1 (SIRT1) play a major role in the modulation of neuroinflammation, oxidative stress and aging-related dopaminergic vulnerability to damage. However, it is not known whether the modulation is related to reciprocal regulation between SIRT1 and AII. In the present study, a single intraventricular injection of AII increased nigral SIRT1 levels in young adult rats. Although AII activity is known to be increased in aged rats, levels of SIRT1 were significantly lower than in young controls. Treatment with the SIRT1-activating compound resveratrol increased nigral SIRT1 levels in aged rats. Levels of SIRT1 were significantly higher in aged wild type mice than in AII type-1 receptor (AT1) deficient mice. In cell culture studies, treatment with AII also induced a transitory increase in levels of SIRT1 in the MES 23.5 dopaminergic neuron and the N9 microglial cell lines. In aged rats, treatment with resveratrol induced a significant decrease in the expression of AT1 receptors and markers of NADPH-oxidase activation (p47phox). In aged transgenic mice over-expressing SIRT1, levels of AT1 and p47 phox were lower than in aged wild type controls. In vitro, the inhibitory effects of resveratrol on AII/AT1/NADPH-oxidase activity were confirmed in primary mesencephalic cultures, the N9 microglial cell line, and the dopaminergic neuron cell line MES 23.5, and they were blocked by the SIRT1 specific inhibitor EX527. The present findings show that SIRT1 and the axis AII/AT1/NADPH-oxidase regulate each other. This is impaired in aged animals and may be mitigated with sirtuin-activating compounds.
authors.affiliation: Laboratory of Neuroanatomy and Experimental Neurology, Dept. of Morphological Sciences, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain.|Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Diaz-Ruiz
authors.affiliation: Laboratory of Neuroanatomy and Experimental Neurology, Dept. of Morphological Sciences, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain.|Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Rodriguez-Perez
authors.affiliation: Department of Physiology, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain.|CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Beiroa
authors.affiliation: Laboratory of Neuroanatomy and Experimental Neurology, Dept. of Morphological Sciences, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain.|Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
authors.forename: Jannette
authors.initials: J
authors.lastname: Rodriguez-Pallares
authors.affiliation: Laboratory of Neuroanatomy and Experimental Neurology, Dept. of Morphological Sciences, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain.|Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Labandeira-Garcia
mesh_terms: D000375:Aging; D000804:Angiotensin II / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000473:pathology*; D002460:Cell Line; D059290:Dopaminergic Neurons / Q000378:metabolism; D005786:Gene Expression Regulation; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D019255:NADPH Oxidases / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D009457:Neuroglia / Q000473:pathology; D009474:Neurons / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000235:genetics*; D013267:Stilbenes / Q000737:chemistry; D013378:Substantia Nigra / Q000378:metabolism*
chemical_list: D044140:Receptor, Angiotensin, Type 1; D013267:Stilbenes; D000804:Angiotensin II; D019255:NADPH Oxidases; C470545:Sirt1 protein, mouse; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D000077185:Resveratrol
keywords: Gerotarget; Parkinson; dopamine; longevity; neuroinflammation; resveratrol