title: Brain angiotensin regulates iron homeostasis in dopaminergic neurons and microglial cells.
abstract: Dysfunction of iron homeostasis has been shown to be involved in ageing, Parkinson's disease and other neurodegenerative diseases. Increased levels of labile iron result in increased reactive oxygen species and oxidative stress. Angiotensin II, via type-1 receptors, exacerbates oxidative stress, the microglial inflammatory response and progression of dopaminergic degeneration. Angiotensin activates the NADPH-oxidase complex, which produces superoxide. However, it is not known whether angiotensin affects iron homeostasis. In the present study, administration of angiotensin to primary mesencephalic cultures, the dopaminergic cell line MES23.5 and to young adult rats, significantly increased levels of transferrin receptors, divalent metal transporter-1 and ferroportin, which suggests an increase in iron uptake and export. In primary neuron-glia cultures and young rats, angiotensin did not induce significant changes in levels of ferritin or labile iron, both of which increased in neurons in the absence of glia (neuron-enriched cultures, dopaminergic cell line) and in the N9 microglial cell line. In aged rats, which are known to display high levels of angiotensin activity, ferritin levels and iron deposits in microglial cells were enhanced. Angiotensin-induced changes were inhibited by angiotensin type-1 receptor antagonists, NADPH-oxidase inhibitors, antioxidants and NF-kB inhibitors. The results demonstrate that angiotensin, via type-1 receptors, modulates iron homeostasis in dopaminergic neurons and microglial cells, and that glial cells play a major role in efficient regulation of iron homeostasis in dopaminergic neurons.
authors.affiliation: Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, Faculty of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Garrido-Gil
authors.forename: Jannette
authors.initials: J
authors.lastname: Rodriguez-Pallares
authors.forename: Antonio
authors.initials: A
authors.lastname: Dominguez-Meijide
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Guerra
authors.forename: Jose L
authors.initials: JL
authors.lastname: Labandeira-Garcia
mesh_terms: D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006706:Homeostasis / Q000502:physiology*; D007501:Iron / Q000378:metabolism*; D008297:Male; D017628:Microglia / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000378:metabolism
chemical_list: D011945:Receptors, Angiotensin; D000804:Angiotensin II; D007501:Iron
keywords: 2′,3′-cyclic nucleotide 3′-phosphodiesterase; AII; Ageing; Ammonium pyrrolidinedithiocarbamate; Ara-C; CNPase; DIV; DMT1; Dopamine; Fp1; IL-1 β; Interleucin 1 β; Microglia; N-acetyl-cysteine; NAC; NADPH-oxidase; NF-kB; Neuroinflammation; Oxidative stress; PD; PDTC; PG-SK; Parkinson's disease; Phen Green-SK; RAS; ROS; Renin–angiotensin system; SN; SN compacta; SNc; TH; Tf; TfR; WB; angiotensin II; cytosine-β-d-arabino-furanoside; days in vitro; divalent metal transporter 1; ferroportin 1; reactive oxygen species; renin–angiotensin system; substantia nigra; transferrin; transferrin receptor; tyrosine hydroxylase; western blot