Alteration of serum/glucocorticoid regulated kinase-1 (sgk-1) gene expression in rat hippocampus after transient global ischemia

doi:10.1016/j.molbrainres.2004.01.008

Molecular Brain Research

Volume 123, Issues 1–2, 7 April 2004, Pages 121-125

https://doi.org/10.1016/j.molbrainres.2004.01.008 Get rights and content

Abstract

Expression of the serum/glucocorticoid regulated kinase-1 (sgk-1) gene has been reported to be induced by various stress stimuli such as hyper- or hypo-osmotic stress, UV irradiation, and heat shock stress; however, its association with global ischemia in the brain has not been studied. Using high-density oligonucleotide array analysis, we found that the sgk-1 gene was one of the genes showing alteration of expression in the rat hippocampus during 1–4 h of reperfusion after 10 min of transient global cerebral ischemia. Using TaqMan RT-PCR analysis, we confirmed an increased level of sgk-1 gene expression with statistical significance in the rat hippocampus at 2 h of reperfusion after 10 min of transient global cerebral ischemia. Using in situ hybridization (ISH) analysis, the increased level of sgk-1 gene expression was found to localize in pyramidal cells of CA2 and CA3 regions of the hippocampus after 2 h of reperfusion. These results provide an insight into the alterations of sgk-1 gene expression in the rat hippocampus after transient global cerebral ischemia.

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Acknowledgements

This work was supported in part by a Nihon University Research Grant for Assistants and Young Researchers (2003) (no. 03-036), by a Nihon University Research Grant for 2002, by a Grant from Nihon University, School of Medicine, as a research award on the 60th anniversary of the founding of Nihon University, School of Medicine, by a Grant-in-Aid (no. 14570777)from the Ministry of Education, Culture, Sports, Science, adn Technology of japan, and by a Grant from the Ministry of Education, Culture,

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Inhibition of serum and glucocorticoid regulated kinases by GSK650394 reduced infarct size in early cerebral ischemia-reperfusion with decreased BBB disruption
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Citation Excerpt :
At two hours of reperfusion after one hour of MCAO, there was a trend of increasing pNDRG1 in the ischemic-reperfused cortex of the control rats, which indicates increased activity of SGK1 by the ischemia-reperfusion. Our data are similar to the reports that SGK1 gene expression is upregulated in the brain global ischemia [31]. Since one of the main substrates of mTORC2 is SGK1, our current study suggests that mTORC2 could have been activated in the stress condition such as ischemia-reperfusion where there is a shortage of energy and imbalance of energy supply and demand [32].
Blood-brain barrier (BBB) disruption is one of the most important pathological changes following cerebral ischemia-reperfusion. We tested whether inhibition of the serum and glucocorticoid regulated kinase 1 (SGK1) would decrease BBB disruption and contribute to decreasing infarct size in the first few hours of cerebral ischemia-reperfusion within the thrombolysis therapy time window. After transient middle cerebral artery occlusion (MCAO), an SGK1 inhibitor GSK650394, or vehicle was administered into the lateral ventricle of rats. After one hour of MCAO and two hours of reperfusion, we determined BBB disruption using the transfer coefficient (K_i) of ¹⁴C-α-aminoisobutyric acid, and also determined infarct size, phosphorylation of NDRG1, and MMP2 protein level. Ischemia-reperfusion increased (+34%, p < 0.05) and GSK650394 decreased (−25%, p < 0.05) the K_i in the ischemic-reperfused cortex. GSK650394 decreased the percentage of cortical infarct (−31%, p < 0.001). At the same time GSK650394 reduced NDRG1 phosphorylation and MMP2 protein level in the ischemic-reperfused cortex suggesting that SGK1 was inhibited by GSK650394 and that lower MMP2 could be one of the mechanisms of decreased BBB disruption. Collectively our data suggest that GSK650394 could be neuroprotective and one of the mechanisms of the neuroprotection could be decreased BBB disruption. SGK1 inhibition within the thrombolysis therapy time window might reduce cerebral ischemia-reperfusion injury.
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SGK1 has been reported to regulate different enzymes, transcription factors, ion channels, transporters, cell proliferation and apoptosis [1,13–16]. SGK1 expression has also been found to be associated with different pathological conditions such as diabetes [17], ischemia [18], cardiac arrhythmia disorders [19] and several cerebral diseases (e.g. Parkinson's disease, Alzheimer's disease, schizophrenia) [20–22]. In addition, SGK1 prevents atrophy [23] and also promotes cell survival under several types of extracellular stresses, including oxidative stress-mediated cellular damages [9,24,25].
Serum- and glucocorticoid-inducible kinase 1 (SGK1), a protein kinase, shares significant structural similarity with other members of the AGC protein kinase family. It has been reported that the inactive SGK1 structure lacks αC helix and this unique feature makes it distinct from other protein kinases. Activation of SGK1 by PDK1 requires phosphorylation at Thr256, but the structural insights of the activation remain unclear. The co-crystal structures of small molecule inhibitors, Magnesium (Mg⁺²) and ATP bound to the inactive SGK1 are reported however the important regulatory domains such as αC helix are missing in these crystal structures. We modelled the missing αC domain and employed computational molecular dynamics simulations to study the conformational changes in the WT and phosphorylated human SGK1 to systematically investigate how the individual domain motions are modulated by the binding of substrate and Mg⁺². The MD results corroborate with the experiential findings and has shown that the inactive SGK1 lacks αC helix content. Surprisingly, we find that the active SGK1 structure closely resembles with other protein kinases and adopt the αC helix content up on SGK1 phosphorylation. However, the residues participating in αC helix formation are fewer than reported in protein kinase A structure, a close relative of SGK1. The computational binding analysis reveals that most of the SGK1 selective inhibitors have less binding affinity for active SGK1 than some FDA-approved kinase inhibitors such as Afatinib, Tofacitinib, Dabrafenib, and Palbociclib. Only EMD638683 was seen as a strong candidate for selective SGK1 inhibition. To our knowledge, this is the first dynamic study of SGK1 that provides new structural insights around the active site that would surely help the experimental biologists for the design of suitable selective ligands able to inhibit or activate SGK1 function.
Social overcrowding as a chronic stress model that increases adiposity in mice
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Sgk1 is transcriptionally regulated by a number of hormones, mediators and stressors (Lang and Stournaras, 2013). Sgk1 gene expressions in the hippocampus and cortex have been shown to be induced by various stressors such as restraint stress, water-immersion and transient ischemia (Nishida et al., 2004; Murata et al., 2005). However, the role of Sgk1 in the hypothalamus is poorly understood.
Stress is a widely recognized risk factor for psychiatric and metabolic disorders. A number of animal models utilizing various stressors have been developed to facilitate our understanding in the pathophysiology of stress-related dysfunctions. The most commonly used chronic stress paradigms include the unpredictable chronic mild stress paradigm, the social defeat paradigm and the social deprivation paradigm. Here we assess the potential of social crowding as an alternative chronic stress model to study the effects on affective behaviors and metabolic disturbances. Ten-week-old male C57BL/6 mice were housed in groups of four (control) or eight (social crowding; SC) in standard cage for 9 weeks. Exploration, anxiety- and depressive-like behaviors were assessed in the open field test, the elevated T-maze, the novelty-suppressed feeding test and the forced swim test. SC mice exhibited a modest anxiety-like phenotype without change in depressive-like behaviors. Nine weeks of social crowding did not affect the body weight, but robustly increased adiposity as determined by increased mass of fat depots. Consistent with the increased fat content, serum leptin was markedly elevated in the SC mice. Specific changes in gene expression were also observed in the hypothalamus and the white adipose tissue following SC housing. Our study demonstrates the potential of social crowding as an alternative model for the study of stress-related metabolic and behavioral dysfunctions.
Up-regulation of serum- and glucocorticoid-induced protein kinase 1 in the brain tissue of human and experimental epilepsy
2010, Neurochemistry International
Citation Excerpt :
This expression trend indicated that SGK1 played more important role in acute damage of epileptic attack. SGK1 expression is regulated during discrete developmental stages and in pathological conditions such as hypertension, diabetic neuropathy, ischemia, trauma, and neurodegenerative diseases (Lang et al., 2006; Nishida et al., 2004; Stichel et al., 2005; Waldegger et al., 1997). Schoenebeck et al. (2005) found SGK1 was up-regulated in various neurotoxic animal models of Parkinson's disease and that the gene seemed to play a key role in protecting neurons.
Several studies have shown that serum- and glucocorticoid-induced protein kinase 1(SGK1) can regulate both glutamate receptors and glutamate transporters and may participate in the regulation of neuroexcitability in neuronal diseases. In our previous study, we analyzed differential gene expression in the anterior temporal neocortex of drug-refractory epilepsy patients relative to control patients using a complementary DNA microarray and found that the SGK1 gene was up-regulated more than twofold in the brain tissues of epileptic patients. In the current study, we measured SGK1 expression in the brain tissues of humans and in an experimental model of rat epilepsy in order to explore the relationship between SGK1 expression and epilepsy. The SGK1 expression was detected in thirty human brain tissues derived from patients undergoing operation for drug-refractory epilepsy and was also detected in eight samples from autopsies. Meanwhile, we investigated SGK1 expression during the epileptic process in rats using immunofluorescence, RT-PCR and western blot analysis. SGK1 expression was enhanced in the temporal neocortex of patients with drug-refractory epilepsy and was also highly expressed in the rat brain during different phases of the epileptic process. SGK1 expression was also related with the elevation of EAAT3, which expression reduced after knockdown SGK1. These results provide new insight into the potential role of SGK1 in the pathophysiology of epilepsy.
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Short communicationAlteration of serum/glucocorticoid regulated kinase-1 (sgk-1) gene expression in rat hippocampus after transient global ischemia

Abstract

Section snippets

Acknowledgements

Brain Res.

J. Biol. Chem.

Mol. Brain Res.

J. Biol. Chem.

Neurochem. Int.

Stimulus-dependent regulation of serum and glucocorticoid inducible protein kinase (SGK) transcription, subcellular localization and enzymatic activity

Cell. Physiol. Biochem.

Thymidylate synthase expression correlates closely with E2F1 expression in colon cancer

Clin. Cancer Res.

Short communication
Alteration of serum/glucocorticoid regulated kinase-1 (sgk-1) gene expression in rat hippocampus after transient global ischemia