SGK1-FoxO1 Signaling Pathway Mediates Th17/Treg Imbalance and Target Organ Inflammation in Angiotensin II-Induced Hypertension.

Ya-Nan Du,Wen-Dong Chen,Lian Xu,Xiao-Feng Tang,Wei-Qing Han,Ping-Jin Gao

doi:10.3389/fphys.2018.01581

Abstract

It has been demonstrated that serum/glucocorticoid regulated kinase 1 (SGK1) and the downstream transcription factor forkhead box O1 (FoxO1) plays a critical role in the differentiation of T helper 17 cells/regulatory T cells (Th17/Treg). In the present study, we hypothesized that this SGK1-FoxO1 signaling pathway is involved in Th17/Treg imbalance and target organ damage in angiotensin II (AngII)-induced hypertensive mice. Results show that SGK1 inhibitor EMD638683 significantly reversed renal dysfunction and cardiac dysfunction in echocardiography as indicated by decreased blood urine nitrogen and serum creatinine in AngII-infused mice. Flow cytometric assay shows that there was significant Th17/Treg imbalance in spleen and in renal/cardiac infiltrating lymphocytes as indicated by the increased Th17 cells (CD4+-IL17A+ cells) and decreased Treg cells (CD4+-Foxp3+). Consistently, real-time PCR shows that Th17-related cytokines including IL-17A, IL-23, and tumor necrosis factor α (TNF-α) was increased and Treg-related cytokine IL-10 was decreased in renal and cardiac infiltrating lymphocytes in AngII-infused mice. Meanwhile, SGK1 protein level, as well as its phosphorylation and activity, was significantly increased in spleen in AngII-infused rats. Furthermore, it was found that splenic phosphorylated FoxO1 was significantly increased, whereas total FoxO1 in nuclear preparation was significantly decreased in AngII-infused mice, suggesting that increased FoxO1 phosphorylation initiate its translocation from cytoplasm to nucleus. Notably, all changes were significantly inhibited by the treatment of EMD638683. These results suggest that SGK1 was involved in Th17/Treg imbalance and target organ damage in AngII-induced hypertension.

Highlights

It has been demonstrated that T lymphocytes play an important role in inflammation and autoimmune diseases (Solak et al, 2016)
We hypothesized that serum/glucocorticoid regulated kinase 1 (SGK1)-forkhead box O1 (FoxO1) signaling pathway is involved in Th17/Treg imbalance, inflammation, and target organ damage in AngIIinfused mice, and that inhibition of SGK1 with EMD638683 would attenuate these changes
These results suggest that SGK1 was not involved in blood pressure increase in angiotensin II (AngII)-infused mice

Summary

Introduction

It has been demonstrated that T lymphocytes play an important role in inflammation and autoimmune diseases (Solak et al, 2016). Th1 cells defend against intracellular pathogens and certain bacteria by directing cell-mediated immunity. SGK1 and Hypertension humoral antibody-mediated immunity fighting against extracellular pathogens and initiating allergic reactions (Yang et al, 2017). Th17 cells are highly pathogenic helper T cells, whereas Treg cells mainly mediate their immune-suppressive effects (Iwakura and Ishigame, 2006; Vignali et al, 2008). Cytokines that activate the transcription factor signal transducer and activator of transcription 3 (STAT3), such as interleukin-6 (IL-6), IL-21, and IL-23, promote Th17 differentiation and inhibit the generation of Treg cells, whereas STAT5-activating cytokines, such as IL-2, have the opposite effects (Noack and Miossec, 2014; Villarino and Laurence, 2015)

Methods

Results

Conclusion