Brain angiotensin regulates iron homeostasis in dopaminergic neurons and microglial cells

Garrido‐Gil, Pablo; Rodríguez‐Pallares, Jannette; Dominguez-Meijide, Antonio; Guerra, María J.; Labandeira‐Garcia, Jose L.

doi:10.1016/j.expneurol.2013.10.013

Cited by 44 publications

(37 citation statements)

References 55 publications

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“…Microglia play a major role in iron storage and homeostasis, and Ang II modulates microglial ferritin/iron storage levels and the neuroinflammatory response (Garrido-Gil et al, 2013a). Microglial ferritin levels (i.e., iron storage by ferritin) change in response to OS and microglial activation, and the release of iron from ferritin in activated microglia may enhance the oxidative damage derived from the proinflammatory microglial response (Mehlhase et al, 2006).…”

Section: Interactions Between Ras and Other Microglial Polarization Rmentioning

confidence: 99%

“…In several studies in aged rats, we observed hyperactivity of the AT1/Nox axis in the substantia nigra, together with an increase in the levels of iron and ferritin, which were inhibited by AT1 receptor blockers such as candesartan. This suggests that overactivity of the Ang II/AT1/Nox axis plays a key role in aging-related iron and ferritin increase in the substantia nigra (Garrido-Gil et al, 2013a). The aging-associated upregulation of Ang II/AT1/Nox activity may lead to upregulation of iron storage by microglia and induce a pro-oxidative pro-inflammatory state and higher vulnerability of dopaminergic cells to degeneration with aging (Collier et al, 2007; Villar-Cheda et al, 2009, 2012b).…”

Section: Interactions Between Ras and Other Microglial Polarization Rmentioning

confidence: 99%

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Brain Renin-Angiotensin System and Microglial Polarization: Implications for Aging and Neurodegeneration

Labandeira‐Garcia

Rodríguez‐Pérez

Garrido‐Gil

et al. 2017

Front. Aging Neurosci.

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Microglia can transform into proinflammatory/classically activated (M1) or anti-inflammatory/alternatively activated (M2) phenotypes following environmental signals related to physiological conditions or brain lesions. An adequate transition from the M1 (proinflammatory) to M2 (immunoregulatory) phenotype is necessary to counteract brain damage. Several factors involved in microglial polarization have already been identified. However, the effects of the brain renin-angiotensin system (RAS) on microglial polarization are less known. It is well known that there is a “classical” circulating RAS; however, a second RAS (local or tissue RAS) has been observed in many tissues, including brain. The locally formed angiotensin is involved in local pathological changes of these tissues and modulates immune cells, which are equipped with all the components of the RAS. There are also recent data showing that brain RAS plays a major role in microglial polarization. Level of microglial NADPH-oxidase (Nox) activation is a major regulator of the shift between M1/proinflammatory and M2/immunoregulatory microglial phenotypes so that Nox activation promotes the proinflammatory and inhibits the immunoregulatory phenotype. Angiotensin II (Ang II), via its type 1 receptor (AT1), is a major activator of the NADPH-oxidase complex, leading to pro-oxidative and pro-inflammatory effects. However, these effects are counteracted by a RAS opposite arm constituted by Angiotensin II/AT2 receptor signaling and Angiotensin 1–7/Mas receptor (MasR) signaling. In addition, activation of prorenin-renin receptors may contribute to activation of the proinflammatory phenotype. Aged brains showed upregulation of AT1 and downregulation of AT2 receptor expression, which may contribute to a pro-oxidative pro-inflammatory state and the increase in neuron vulnerability. Several recent studies have shown interactions between the brain RAS and different factors involved in microglial polarization, such as estrogens, Rho kinase (ROCK), insulin-like growth factor-1 (IGF-1), tumor necrosis factor α (TNF)-α, iron, peroxisome proliferator-activated receptor gamma, and toll-like receptors (TLRs). Metabolic reprogramming has recently been involved in the regulation of the neuroinflammatory response. Interestingly, we have recently observed a mitochondrial RAS, which is altered in aged brains. In conclusion, dysregulation of brain RAS plays a major role in aging-related changes and neurodegeneration by exacerbation of oxidative stress (OS) and neuroinflammation, which may be attenuated by pharmacological manipulation of RAS components.

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Section: Interactions Between Ras and Other Microglial Polarization Rmentioning

confidence: 99%

Section: Interactions Between Ras and Other Microglial Polarization Rmentioning

confidence: 99%

Brain Renin-Angiotensin System and Microglial Polarization: Implications for Aging and Neurodegeneration

Labandeira‐Garcia

Rodríguez‐Pérez

Garrido‐Gil

et al. 2017

Front. Aging Neurosci.

Self Cite

193

195

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“…ROS production by nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) and the activation of redox-dependent signaling cascades by Ang II are considered critical processes underlying neuronal-vascular injury and inflammation [9,10]. Further, an increasing number of reports demonstrate that Ang II induces iron accumulation in several tissues, including the aorta and neuronal tissue [11]. This might play a role in the impairment of vascular function and arterial remodeling induced by Ang II, possibly by enhancing iron-dependent oxidative stress [12].…”

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confidence: 99%

JNK/p66Shc/ITCH Signaling Pathway Mediates Angiotensin II-induced Ferritin Degradation and Labile Iron Pool Increase

et al. 2020

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Angiotensin II (Ang II) induces deleterious changes in cellular iron metabolism and increases the generation of reactive oxygen species. This leads to an impairment of neuronal and vascular function. However, the mechanism underpinning Ang II-induced changes in iron metabolism is not known. We hypothesized that Ang II-induced ferritin degradation and an increase in the labile iron pool are mediated by the c-Jun N-terminal kinase (JNK)/p66Shc/ITCH signaling pathway. We show that Ang II treatment induced ferritin degradation in an endothelial cell lines derived from the bovine stem pulmonary artery (CPAE), human umbilical vein endothelial cells (HUVEC), and HT22 neuronal cells. Ferritin degradation was accompanied by an increase in the labile iron pool, as determined by changes in calcein fluorescence. The JNK inhibitor SP600125 abolished Ang II-induced ferritin degradation. Furthermore, the effect of Ang II on ferritin levels was completely abolished in cells transfected with vectors encoding catalytically inactive variants of JNK1 or JNK2. CPAE cells expressing inactive ITCHor p66Shc (substrates of JNK kinases) were completely resistant to Ang II-induced ferritin degradation. These observations suggest that Ang II-induced ferritin degradation and, hence, elevation of the levels of highly reactive iron, are mediated by the JNK/p66Shc/ITCH signaling pathway.Nutrients 2020, 12, 668 2 of 12 Vascular diseases are associated with an increase in the production of reactive oxygen species (ROS) in the vessel wall and with endothelial dysfunction. It is generally assumed that increased ROS levels, particularly superoxide (O 2 .-) levels, on the one hand reduce nitric oxide (NO) bioavailability and on the other give rise to deleterious peroxynitrite. Ang II is a well-known inducer of endothelial cell activation and smooth muscle cell proliferation resulting from ROS-induced signal transduction [7,8]. ROS production by nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) and the activation of redox-dependent signaling cascades by Ang II are considered critical processes underlying neuronal-vascular injury and inflammation [9,10]. Further, an increasing number of reports demonstrate that Ang II induces iron accumulation in several tissues, including the aorta and neuronal tissue [11]. This might play a role in the impairment of vascular function and arterial remodeling induced by Ang II, possibly by enhancing iron-dependent oxidative stress [12]. In addition, iron chelation suppresses Ang II-induced upregulation of TGF-β1 in the heart and attenuates vascular dysfunction in the aorta [13,14]. The majority of intracellular iron is stored by ferritin, a protein composed of L and H subunits. Ferritin-stored iron is considered to be safe (inert), as it does not participate in free radical-generating reactions, e.g., the Fenton reaction and others. Hence, the iron-dependent formation of ROS is associated with the levels of free iron bound to low-molecular weight compounds, such as nucleotides and amino acids, etc. Th...

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“…It is widely known that activation of microglia, in response to illness, infection and injury, lead to morphological changes, from the highly ramified configuration to a globular, amoeboid shape (Kitamura et al 1978;Stence et al 2001;Thomas 1992). Activated microglia demonstrate increased proliferation, migration to the site of injury, scavenging of exogenous substances, cellular debris and pathogens, and production of proinflammatory molecules, including cytokines, chemokines, prostaglandins, nitric oxide and reactive oxygen species (Suzuki et al 2004;Hide et al 2000;Koizumi et al 2007;Stence et al 2001;Nolte et al 1996;Morioka et al 2013;Garrido-Gil et al 2013;Fernandes et al 2014). Cells that exhibit this phenotype are identified as "M1 microglia" (Kigerl et al 2009).…”

Section: Neuroinflammatory and Neuroprotective Roles Of Microgliamentioning

confidence: 99%

Nicotinic Acetylcholine Receptor Signaling in Neuroprotection

Akaike

Shimohama

Misu

2018

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Brain angiotensin regulates iron homeostasis in dopaminergic neurons and microglial cells

Cited by 44 publications

References 55 publications

Brain Renin-Angiotensin System and Microglial Polarization: Implications for Aging and Neurodegeneration

Brain Renin-Angiotensin System and Microglial Polarization: Implications for Aging and Neurodegeneration

JNK/p66Shc/ITCH Signaling Pathway Mediates Angiotensin II-induced Ferritin Degradation and Labile Iron Pool Increase

Nicotinic Acetylcholine Receptor Signaling in Neuroprotection

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