SGK-1 (Serum- and Glucocorticoid-Inducible Kinase-1)
The serum- and glucocorticoid-inducible kinase-1 (SGK-1) was originally cloned in 1993 by Webster et al., as an immediate early gene transcriptionally stimulated by serum and glucocorticoids in rat mammary tumor cells (Webster et al. 1993a, b). Few years later, the human isoform was cloned and characterized as a putative serine/threonine protein kinase transcriptionally modified during alterations of cell volume in human hepatoma cell line (Waldegger et al. 1997). The gene encoding human SGK-1 was localized to chromosome 6q23 (Waldegger et al. 1998). Subsequently were identified two novel isoforms homologous of SGK-1, the SGK-2 and SGK-3, that share 80% amino acid sequence identity in their catalytic domain with SGK-1 (Kobayashi et al. 1999). SGK kinases are expressed in a wide variety of species such as Caenorhabditis elegans and yeast that express two orthologs, Ypk1 and Ypk2 (Lauro et al. 2015). In mammals, SGK-1 is ubiquity expressed in tissues with the highest levels in the pancreas, liver, and heart (Waldegger et al. 1998).
Modulation of SGK-1 Transcription and Activity
The SGK-1 gene encodes a 49/50 kDa protein that is a member of the “AGC” family of serine/threonine protein kinases. SGK-1 contains a catalytic domain that is approximately 45–55% homologous to the catalytic domains of other different serine/threonine protein kinases, such as protein kinase B (Akt/PKB), protein kinase A (PKA), protein kinase C-zeta (PKC-zeta), and rat p70 S6 kinase (Firestone et al. 2003). SGK-1 is characterized by a stringent stimulus-dependent regulation of its transcription, enzymatic activity, and subcellular localization (Firestone et al. 2003). Transcription of SGK-1 is upregulated by both serum and glucocorticoids and different hormones such as mineralocorticoid, growth factors, and environmental signals (specifically, stress signals) that induce expression of a catalytically active SGK-1 (transcription regulation). SGK-1 transcription is also stimulated by excessive glucose concentrations, heat shock, ultraviolet (UV) radiation, and oxidative stress (Lang et al. 2006). SGK-1 acts as a stressor kinase reacting to a specific input in which the cell or tissue system is in a dangerous metabolic condition. The promoter of the rat SGK-1 gene is characterized by different transcription factor-binding sites such as those for the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), the cAMP response element-binding protein (CREB), and the nuclear factor кB (NFкB) (Lang et al. 2006), suggesting a multiple regulation in its transcription. It is important to consider that the modulation of SGK-1 transcription levels is unstable; therefore, there is a continuous replacement of the protein in the tissue which is pivotal for its function (Lang et al. 2006).
SGK-1 Molecular Function
SGK-1 Regulates Apoptosis and Oxidative Stress
Increasing evidence in both experimental and clinical studies suggests that oxidative stress plays a major role in the pathogenesis of many diseases, such as diabetes mellitus and cardiovascular disease. Stimulation of SGK-1 expression is a common downstream target of heat shock, UV irradiation, and in particular oxidative stress, in mammary epithelial cells (Firestone et al. 2003). The effects of oxidative stress, on SGK-1 cellular activation, were initially investigated in NMuMg mammary epithelial cells exposed to hydrogen peroxide (H2O2) (Leong et al. 2003). This stress stimulated SGK-1 expression through a p38/MAPK-dependent pathway and induced the activation and consequent phosphorylation of SGK-1. These studies established the pivotal role of the induction of enzymatically active SGK-1 function as a key cell survival component in response to oxidative stress (Fig. 2) (Leong et al. 2003). Upregulation of SGK-1 induced by oxidative stress may reflect a protective and adaptive cellular response against noxious stimuli. Additional experimental studies conducted in an in vitro model of endothelial cells demonstrated that SGK-1 is protective against hyperglycemia-induced oxidative stress via reactive oxygen species (ROS), synthesis inhibition, and increase of nitric oxide (NO) (Ferrelli et al. 2015; Lauro et al. 2015).
SGK-1 and Its Role in Diseases
SGK-1 and Diabetes
Type 2 diabetes mellitus (T2D) is a pathological condition characterized by hyperglycemia, subsequent to insulin resistance (IR), and an impairment in glucose-mediated insulin secretion. Recent studies showed an interesting role of SGK-1 in the pathophysiology of diabetes and its complications (Ferrelli et al. 2015; Schwab et al. 2008). The most interesting evidence comes from a study conducted in rat insulinoma (INS1) cells, which demonstrated that SGK-1 mediates the inhibition of insulin secretion, glucocorticoid-induced, upregulating the activity of voltage-gated K+ channels and consequently reducing Ca2+ entry through voltage-gated Ca2+ channels and insulin release. This finding suggests that SGK-1 participates in the downregulation of insulin secretion mediated by glucocorticoid. These results are in agreement with the role of this kinase as stressor protein’s response, since activation by glucocorticoids increases circulating glucose by decreasing insulin (Ullrich et al. 2005). SGK-1 is able to upregulate GLUT1 expression and activity by phosphorylating Ser95, suggesting a physiological role of SGK-1 in glucose transport regulation. Reduction in glucose transport, in fact, was observed in adipocytes isolated from sgk-1−/− mice (Lauro et al. 2015). Moreover, liver-specific sgk-1−/− mice develop glucose intolerance and IR, while overexpression of SGK-1 significantly ameliorates insulin sensitivity (Liu et al. 2014). Few studies investigated so far the association between SGK-1 and diabetes in humans, and only one reported the relationship between SGK-1 genetic variants, specifically a polymorphism in intron 6 (I6CC) and in exon 8 (E8CC/CT), and T2D, in a small population cohort (Schwab et al. 2008). Moreover, since SGK-1 stimulates Na+-coupled glucose transporter (SGLT1), SGK-1 genetic variants may further accelerate the intestinal glucose absorption mediated by SGLT1, leading to excessive insulin release and fat deposition (Lauro et al. 2015).
SGK-1 and Hypertension
Hypertension is an alteration due to failure of kidney function, vascular hypertrophy, and stiffening of the arterial wall. One of the most important molecules, along with Akt-1, involved in the control of sodium reabsorption and release of nitric oxide (NO), is SGK-1. SGK-1 contributes to the stimulation of renal Na+ reabsorption and excretion induced by hormone stimuli such as aldosterone, insulin, and IGF1. SGK-1 regulates transcription and activity of epithelial sodium channel protein ENaC in the apical tubule of distal nephron, mediated by aldosterone stimuli, determining the excretion of Na+ and K+. ENaC could be modulated by SGK-1 through different pathways (Fig. 3):
The Nedd4-2 (neural precursor cell expressed, developmentally downregulated 4-2) phosphorylation removes tonic inhibition of ENaC-mediated Nedd4-2 and enhances sodium transport. In fact, Nedd4-2 maintains the plasma membrane levels of ENaC, modulating its degradation mediated by proteasome (Fig. 3) (Lauro et al. 2015).
SGK-1 also modulates ENaC activity inducing the transcription of different consensus sequences.
SGK-1 phosphorylates ENaCα transcription factor Af9 (ALL1-fused gene from chromosome 9) activating ENaCα gene transcription, induced by aldosterone stimuli. In basal condition, Af9 binds Dot1a (the histone H3 Lys79 methyltransferase disruptor of telomeric silencing alternative splice variant a), generating a nuclear repressor complex that inhibits the basal ENaCα transcription (Fig. 3) (Lang et al. 2006; Zhang et al. 2007).
The role of SGK-1 in the pathophysiology of Na+ retention was mainly investigated by using sgk-1−/− mice model. A small increase of renal salt retention was observed in sgk-1−/− and wild-type mice fed with high-salt diet because augmented levels of aldosterone modified arterial blood pressure and renal salt output. Despite hyperaldosteronism, a low-salt intake induced in sgk-1−/− mice an insufficient renal NaCl retention and increased levels of Na+ reabsorption in proximal tubule (Fejes-Toth et al. 2008).
During dehydration conditions, enhanced osmolarity induced SGK-1 overexpression, which in turn increased natriuretic peptide receptor levels and then raised Na+ output. As previously reported, SGK-1 can regulate several channels as NaCl cotransporter (NCC), Ca2+ channel TRPV5, K+ channel ROMK1, and glucose transporter SGLT1. During K+ excretion, SGK-1 induces renal K+ elimination generated by ENaC and Na-K-ATPase activity, interacting with body fluid control and then with blood pressure.
Moreover, SGK-1 is involved also in renal Ca2+ excretion: in fact, a lower expression of Ca2+ channel TRPV5 was observed in sgk-1−/− mice. Impairment in NaCl cotransport and ENaC activation was observed in a condition of SGK-1 inactivation, leading to a reduction in extracellular volume consequently to renal salt loss (Lang et al. 2006).
SGK-1 expression in the proximal tubule is low in normal kidneys and may not affect ionic transport. Moreover, SGK-1 expression can be induced by hyperglycemia in proximal tubule, by aldosterone and oxidative stress in glomerular podocytes (Shibata et al. 2007). The aldosterone/MR signaling activation can regulate the balance between Na+ reabsorption and K+ secretion through the interaction between SGK-1 and serine/threonine protein kinase WNK4: this pathway is very important since it is primarily responsible for hypertension and renal fibrosis (Lauro et al. 2015).
SGK-1 and Neurodegeneration
SGK-1 plays a key role in the central nervous system, especially during learning and memory processes, long memory consolidation, and modulation of synaptic plasticity. In Parkinson disease (PD), the principal cause of symptoms is the progressive loss of dopamine-producing neurons. SGK-1 is able to block neurons death by inactivating proapoptotic action of FOXO3a (Fig. 4) (Schoenebeck et al. 2005). However, the protective function of SGK-1 is not only mediated by regulation of FOXO3a but also by stimulating transcription of voltage-gated potassium (Kv) channels that are physiological substrates of SGK-1 in vivo (Lauro et al. 2015). In experimental animal models, treatment with MPTP (1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine) to induce PD generated a decrease in the expression of Kv1.1, Kv1.2, and Kv1.3, leading to a harmful neuronal hyperexcitability and consequent apoptosis of neurons (Schoenebeck et al. 2005). Neuronal cells from Alzheimer’s disease (AD) patients show that active SGK-1 protects and exerts antiapoptotic effects from harmful stimuli via transcription factor FOXO3a (Fig. 4). SGK-1 has reported to be expressed in cortical pyramidal neurons of aged human brain. In cortical neurons of AD brain, SGK-1 had a higher nuclear expression and activation, confirmed by increased levels of NDRG1 phosphorylation, which is an SGK-1 substrate. Moreover, the fraction of cortical neuron containing nuclear FOXO3a is lower in AD brain, since SGK-1 blocks FOXO3a action by phosphorylation, inducing cytoplasmic shuttle (Sahin et al. 2013; Lauro et al. 2015). SGK-1 has shown to play an important function also in Huntington disease (HD). This disorder is characterized by accumulation of mutated huntingtin (formed by a long tail of polyQ) (Fig. 4). SGK-1 phosphorylates mutated huntingtin at Ser421, protecting striatal neurons against polyQ-huntingtin-induced toxicity by p38/MAPK pathway (Fig. 4) (Rangone et al. 2004). An interruption in blood flow to the brain (cerebral ischemia) for more than few minutes results in irreversible brain damage, typically identified as a stroke. Neurons are highly vulnerable to ischemia, in particular those in the hippocampus among the most affected. Particularly, following global cerebral ischemia/reperfusion (I/R) increased SGK-1 expression was observed in the rat hippocampus, while it was also upregulated after focal neuronal injury. Recently, a protective effect of SGK-1 was also shown in neurons subjected to hypossia and ischemia by using oxygen and glucose deprivation (OGD) and middle cerebral artery occlusion (MCAO) as models of neuronal injuries (Lauro et al. 2015). Rat hippocampal neurons apoptosis is greatly increased by OGD and continued to increase during reperfusion time. SGK-1 overexpression reduced considerably the apoptosis after OGD insult, by activating PI3K/Akt/GSK-3β pathway. These results were confirmed also in vivo in adult male rats subjected to MCAO, suggesting that SGK-1 agonists may be a novel target to reduce brain injury if administered in patients within a few hours from ischemic attack onset (Lauro et al. 2015).
SGK-1 is a pleiotropic protein kinase that plays an important role in cellular stress response. It is a kinase transcriptionally stimulated by serum and glucocorticoids and is activated and phosphorylated by insulin and growth factors via PI3K pathway. One of the SGK-1 characteristics is the rapid protein’s degradation by the proteasome 26S; this kinase presents a half-life of 30 min. Relevant studies demonstrated that increase in SGK-1 expression and activity protects endothelial cells by oxidative stress and apoptosis and improves NO production after hyperglycemic insult. SGK-1 has been shown to be strongly involved in mechanisms associated with homeostasis of body fluid and then with the hypertension by regulating different kidney channels. Moreover, SGK-1 is involved in neurodegeneration by inactivating FOXO3a and decreasing neuronal apoptosis and hyperexcitability by controlling gene expression of Kv channels. Therefore, SGK-1 may represent a specific molecular target to develop novel therapeutic strategies against diabetic vascular disease or prevent neurodegenerative pathologies. Consequently, advanced studies to clarify the role played by SGK-1 in different pathophysiological processes are needed to identify the potential of this remarkable kinase.
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