Serum glucocorticoid inducible kinase (SGK)-1 protects endothelial cells against oxidative stress and apoptosis induced by hyperglycaemia

Abstract

Diabetic hyperglycaemia causes endothelial dysfunction mainly by impairing endothelial nitric oxide (NO) production. Moreover, hyperglycaemia activates several noxious cellular pathways including apoptosis, increase in reactive oxygen species (ROS) levels and diminishing Na(+)-K(+) ATPase activity which exacerbate vascular damage. Serum glucocorticoid kinase (SGK)-1, a member of the serine/threonine kinases, plays a pivotal role in regulating NO production through inducible NO synthase activation and other cellular mechanisms. Therefore, in this study, we aimed to investigate the protective role of SGK-1 against hyperglycaemia in human umbilical endothelial cells (HUVECs). We used retrovirus to infect HUVECs with either SGK-1, SGK-1Δ60 (lacking of the N-60 amino acids-increase SGK-1 activity) or SGK-1Δ60KD (kinase-dead constructs). We tested our hypothesis in vitro after high glucose and glucosamine incubation. Increase in SGK-1 expression and activity (SGK-1Δ60) resulted in higher production of NO, inhibition of ROS synthesis and lower apoptosis in endothelial cell after either hyperglycaemia or glucosamine treatments. Moreover, in this study, we showed increased GLUT-1 membrane translocation and Na(+)-K(+) ATPase activity in cell infected with SGK-1Δ60 construct. These results suggest that as in endothelial cells, an increased SGK-1 activity and expression reduces oxidative stress, improves cell survival and restores insulin-mediated NO production after different noxae stimuli. Therefore, SGK-1 may represent a specific target to further develop novel therapeutic options against diabetic vascular disease.

Elevated expression of glucocorticoid-induced leucine zipper in placental endothelial and trophoblastic cells in preeclampsia

“…There are studies that have shown that glucocorticoids cause endothelial damage and function deterioration and those that use glucocorticoid in the treatment of endothelial damage. [12,13] GILZ is a gene of the TSC-22 protein family, which is inducible by dexamethasone and characterized by the presence of TSC box and leucine. [14] GILZ's roles in mediating anti-inflammatory effects of glucocorticoids are shown invariouscell types.…”

Serum- and Glucocorticoid-Inducible Kinase 1 Delay the Onset of Endothelial Senescence by Directly Interacting with Human Telomerase Reverse Transcriptase

“…In our previous study, we demonstrated a protective role of SGK1 against hyperglycaemia by decreasing ROS production in young HUVEC (3). Therefore, we sought to investigate whether a similar effect of SGK1 was present in aged endothelial cells.…”

“…In our previous in vitro study, by using young Human Umbilical Vein Endothelial Cells (HUVEC), we demonstrated, as SGK1 overexpression was protective against hyperglycaemia by inhibiting ROS synthesis, and lowering cellular apoptosis (3). Particularly, we showed as both SGK1 Wild Type (WT), and SGK1Δ60 (lacking of the N-60 amino acids-increase SGK1 activity) were protective against diabetic vascular disease in young HUVEC (3). Based on the physiological role of SGK1 in cell cycle progression (4) and cell survival pathways (5), SGK1 has been proposed for age-related processes in different organs, such as brain (5) and skin (6).…”

Global gene expression profiling using heterologous DNA microarrays to analyze alterations in the transcriptome of Mus spretus mice living in a heavily polluted environment

“…The Sgk1 gene codes for a serum/glucocorticoid-regulated kinase, SGK1, involved in protective mechanisms against oxidative stress-mediated cellular damages and apoptosis (Ferrelli et al 2014). Overexpression of SGK-1 reduces ROS levels in SOD1 knockout mice, which is in agreement with the observed increase of the Sgk mRNA (8419-fold) that we saw in the DRS mice.…”