Role of Serum and Glucocorticoid-Inducible Kinase (SGK)-1 in Senescence: A Novel Molecular Target Against Age-Related Diseases

Abstract

Senescence is a phenomenon characterized by a progressive decline of body homeostasis. Premature senescence acts when the cellular system is not able to adequately respond to noxious stimuli by synthesis of stressor molecules. Among those, serum-and-glucocorticoidinducible kinase-1 (SGK-1) dramatically increases under typical physiopathological conditions, such as glucocorticoid or mineralcorticoids exposure, inflammation, hyperglycemia, and ischemia. SGK-1 has been implicated in mechanism regulating oxidative stress, apoptosis, and DNA damage, which are all leading to a state of accelerating aging. Moreover, SGK-1-sensitive ion channels participate in the regulation of renal Na(+)/K(+) regulation, blood pressure, gastric acid secretion, cardiac action potential, and neuroexcitability. Recently, we demonstrated in endothelial cells as an increase in SGK-1 activity and expression reduces oxidative stress, improves cell survival and restores insulin-mediated nitric oxide production after hyperglycemia. Moreover, we showed as SGK-1 delays the onset of senescence by increasing telomerase activity, significantly decreasing reactive oxygen species (ROS) production, and by directly interacting with hTERT. Therefore, SGK-1 may represent a specific target to further develop novel therapeutic options against chronic diseases such as diabetes typical of aging. SGK-1 has been also associated with cancer, neurodegenerative diseases, and cardiovascular disease, among other age-related diseases. However, to date, the data available on SGK-1 and aging, are sparse, controversial, and only from C. elegans experimental models. In this review we sought to discuss the possible implication of SGK-1 in mechanisms regulating senescence and age-related diseases. Moreover, we aimed to discuss and identify the possible role of SGK-1 as possible molecular target to counteract and prevent aging.

Associations of the Serum/Glucocorticoid Regulated Kinase Genes With BP Changes and Hypertension Incidence: The Gensalt Study

“…Furthermore, physiological studies have demonstrated the involvement of SGK1 in regulating tissue inflammation with known contribution to hypertension pathophysiology. 19,20 In aggregate, these data provide strong evidence for a role of SGK1 in hypertension development.…”

“…17,18 Recent in vitro and in vivo studies showed that SGK1 can promote tissue inflammation and cell senescence, providing a new insight into BP regulation. 19,20 Similar to SGK1, SGK2, and SGK3 can also influence Na+/H+ exchanger 3 activity and potentially regulate Na+ transport. 8 SGK's biological relevance along with evidence from in vitro and in vivo studies make the SGK genes important candidates for genetic study of BP phenotypes.…”

Axonal and Myelin Neuroprotection by the Peptoid BN201 in Brain Inflammation

“…mRNA levels of CNTF (C), SESN3 (D), and iNOS (E) in the brain homogenates from mice treated with BN201 for 5 days (black line) and the corresponding BN201 CNS levels (in red). *p < 0.05 day 5, 10, or 15 with respect to day 0 of the same treatment group, ANOVA test Previous studies have shown neurotrophic effects of SGK1, including the induction of neuronal hypertrophy, protection from neuron death and axonal degeneration, and axonal regeneration [43,52,53]. Moreover, MDK also displays prosurvival neuronal effects and protects myelin-forming cells [54,55].…”

“…Analysis of proteinprotein interaction databases pointed to the activation of the midkine-nucleolin-PTGES3 axis, like the SGK pathway, which participates in the trophic factor pathway (PI3K-AKT pathway) and protects neurons against damage (e.g., kainic acid-induced seizures, ischemia, or amyloid beta toxicity) [41]. SGKs are expressed strongly in all types of neurons and it is considered to be a stress sensor [42], promoting the expression of antioxidant enzymes and the modulation of ion channels [43], as well as participating in trophic factor pathways (e.g., insulin growth factor 1 (IGF-1) receptor pathway), promoting neuronal survival. Indeed, MDK also activates the IGF-1 pathway.…”

Inactivation of SREBP-1a Phosphorylation Prevents Fatty Liver Disease in Mice: Identification of Related Signaling Pathways by Gene Expression Profiles in Liver and Proteomes of Peroxisomes

“…In line with a previous report of a protective effect of endogenous catalase activity in fatty liver [ 42 ], a further novel finding of our study was the observation that half of the genes that center around SREBP-1 and differ in regulation according to the ability of SREBP-1a to be phosphorylated are correlated with peroxisomal catalase activity. These included genes like CWF19L1, which was previously shown to act in fatty liver and metabolic diseases [ 43 , 44 , 45 , 46 ]. Furthermore Lcn2 (lipocalin-2) correlated to catalase activity dependent on SREBP-1a phosphorylation.…”