Astrocyte Resilience to Oxidative Stress Induced by Insulin-like Growth Factor I (IGF-I) Involves Preserved AKT (Protein Kinase B) Activity

Abstract

Disruption of insulin-like growth factor I (IGF-I) signaling is a key step in the development of cancer or neurodegeneration. For example, interference of the prosurvival IGF-I/AKT/ FOXO3 pathway by redox activation of the stress kinases p38 and JNK is instrumental in neuronal death by oxidative stress. However, in astrocytes, IGF-I retains its protective action against oxidative stress. The molecular mechanisms underlying this cell-specific protection remain obscure but may be relevant to unveil new ways to combat IGF-I/insulin resistance. Here, we describe that, in astrocytes exposed to oxidative stress by hydrogen peroxide (H 2 O 2 ), p38 activation did not inhibit AKT (protein kinase B) activation by IGF-I, which is in contrast to our previous observations in neurons. Rather, stimulation of AKT by IGF-I was significantly higher and more sustained in astrocytes than in neurons either under normal or oxidative conditions. This may be explained by phosphorylation of the phosphatase PTEN at the plasma membrane in response to IGF-I, inducing its cytosolic translocation and preserving in this way AKT activity. Stimulation of AKT by IGF-I, mimicked also by a constitutively active AKT mutant, reduced oxidative stress levels and cell death in H 2 O 2 -exposed astrocytes, boosting their neuroprotective action in co-cultured neurons. These results indicate that armoring of AKT activation by IGF-I is crucial to preserve its cytoprotective effect in astrocytes and may form part of the brain defense mechanism against oxidative stress injury. IGF-I2 is a pleiotropic growth factor with important prosurvival effects in neurons (1). One of the main downstream targets of IGF-I is the Ser/Thr kinase AKT (2), which mediates cell survival and proliferation (3). Upon its activation, the IGF-I receptor recruits and phosphorylates IRS docking proteins (4), which allows translocation of phosphatidylinositol 3-kinase (PI3K) to the plasma membrane where it catalyzes the formation of the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ) (5). AKT is recruited to the membrane by interaction with these messengers so that it can be fully activated by PDK1 and mTORC2 kinases (3,6). This pathway is switched off (to prevent uncontrolled proliferation) through activation of the lipid and protein phosphatase PTEN, which catalyzes PIP 3 dephosphorylation (4).Cell metabolism generates potentially harmful reactive oxygen species (ROS), which at moderate levels can act as second messengers (7). However, chronic and/or abrupt increases of ROS (uncontainable by detoxification through cellular defenses) generates oxidative stress, a pathological cellular condition that can interfere with redox-sensitive signaling pathways (7). Neurons are particularly vulnerable to oxidative stress because of their low ROS detoxifying capacity (8).We previously described that oxidative stress interferes with the IGF-I/PI3K/AKT pathway by redox activation of p38 kinase to induce neuronal death (9). IGF-I signaling impairment by oxidative stress ha...

Neuroglobin protects astroglial cells from hydrogen peroxide‐induced oxidative stress and apoptotic cell death

“…It is well‐known that astroglial cells contain high levels of ROS scavenger molecules that play a prominent role in the protection of neurons against oxidative stress injuries (Hansson and Ronnback ; Davila et al . ). In addition, astrocytes contribute to the defense of neighboring neurons by providing trophic support and substrates for antioxidant molecules such as glutathione (Lee et al .…”

Acute Ethanol Increases IGF‐I‐Induced Phosphorylation of ERKs by Enhancing Recruitment of p52‐Shc to the Grb2/Shc Complex

“…In the brain, the IGF‐IR is abundantly expressed during embryonic and postnatal development, but its expression declines significantly during adolescence and adult life (Bondy and Lee, ). Early studies regarding the expression patterns of the IGF‐IR were followed by numerous studies providing overwhelming evidence for the role of the IGF‐IR in protecting neurons from oxidative stress (Heck et al, ; Davila and Torres‐Aleman, ; Davila and Fernandez, ), high glucose (Russell and Feldman, ), nitric oxide (Zheng et al, ), and TNFα (Ying Wang et al, ; Wang et al, ). In transgenic models, mice overexpressing IGF‐I demonstrated an increase in brain weight, which was significantly larger than the corresponding increase in total body weight (Mathews et al, ; Reiss et al, ; Popken et al, ).…”

Disparate Central and Peripheral Effects of Circulating IGF-1 Deficiency on Tissue Mitochondrial Function

“…IGF-1 has been shown to induce alterations in mitochondrial function [32] and protect against oxidative stress via sustained AKT activation [29,30]. To assess mitochondrial function, we isolated mitochondria from 18-month GFP and LID hippocampi and measured oxygen consumption rate (OCR) and hydroperoxide production rate using O2K HRR.…”

“…While reduction in IGF-1 peripherally protects against the onset and progression of specific types of cancer [14] and modestly increases lifespan in a sex-dependent manner, deficiency of IGF-1 availability in the brain by ectopic expression of IGF-1 binding protein (IGFBP-1) has been shown to reduce astrocytic response to injury [28]. IGF-1 has also been shown to protect neurons against oxidative stress via modulation of astrocytic responses [29,30]. IGF-1 signaling regulates ATP production in aging mice [31] and has recently been shown to affect mitochondrial dynamics in astroglial cells [32].…”