Brain angiotensin regulates iron homeostasis in dopaminergic neurons and microglial cells.
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.
['Garrido-Gil|Pablo|P|', 'Rodriguez-Pallares|Jannette|J|', 'Dominguez-Meijide|Antonio|A|', 'Guerra|Maria J|MJ|', 'Labandeira-Garcia|Jose L|JL|']
D000804:Angiotensin II D000818:Animals D015153:Blotting, Western D001921:Brain D002478:Cells, Cultured D059290:Dopaminergic Neurons D005455:Fluorescent Antibody Technique D006706:Homeostasis D007501:Iron D008297:Male D017628:Microglia D051381:Rats D017207:Rats, Sprague-Dawley D011945:Receptors, Angiotensin
Ageing Parkinson's disease reactive oxygen species Oxidative stress angiotensin II NADPH-oxidase transferrin transferrin receptor NF-kB 2′,3′-cyclic nucleotide 3′-phosphodiesterase AII Ammonium pyrrolidinedithiocarbamate Ara-C CNPase DIV DMT1 Dopamine Fp1 IL-1 β Interleucin 1 β Microglia N-acetyl-cysteine NAC Neuroinflammation PD PDTC PG-SK Phen Green-SK RAS ROS Renin–angiotensin system SN SN compacta SNc TH Tf TfR WB cytosine-β-d-arabino-furanoside days in vitro divalent metal transporter 1 ferroportin 1 renin–angiotensin system substantia nigra tyrosine hydroxylase western blot