The Modulation of Regulatory T Cells via High Mobility Group Box-1/Receptor for Advanced Glycation End-Products/Adenosine Monophosphate-Activated Protein Kinase Axis in Chronic Kidney Diseases with Complication of Sepsis

Abstract

Chronic kidney diseases (CKD) with complication of sepsis brings great clinical burden worldwide. Regulatory T cells (Tregs) can regulate key immune response during the progression of the diseases. The present study aims to investigate the role of HMGB1 in the regulation of Tregs and find out the potential mechanism. Jurkat cells were stimulated with 0.5 ng/ml TGF-β1 for 24 h to induce phenotypic alternation into Tregs, followed by stimulation with indoxyl sulfate (IS) and lipopolysac-charide (LPS) for 24 h. Then, Tregs were treated with recombinant human HMBG1 (rHMGB1) at different concentrations (10, 100 and 1000 ng/ml). Cell viability of Tregs was assayed by CCK-8. The gene expressions related to proliferation and autophagy were determined using RT-qPCR and western blotting. RAGE was inhibited by transfection with shRNA-RAGE in Tregs. The results showed that HMGB1 and RAGE were upregulated upon IS and LPS induction in Tregs. rHMGB1 significantly promoted the viability, proliferation and function of Tregs at a concentration-dependent way, which was partly reversed by RAGE knockdown. Besides, HMGB1-RAGE could regulate autophagy activity and AMPK-mTOR signaling pathway. In summary, our study concluded that the active autophagy mediated by enhanced HMGB1-RAGE axis through AMPK-mTOR signaling pathway was a potential mechanism to enhance Tregs viability and function in chronic kidney diseases with complication of sepsis.