AGEs-RAGE-KCa3.1 pathway mediates palmitic acid-induced migration of PBMCs from patients with type 2 diabetes

Yi Zhang; Xiao-Zhen Ma; Xin-Yi Zhao; Jing-Jing Li; Shan Ma; Zheng-Da Pang; Jing Xu; Xiao-Jun Du; Xiu-Ling Deng; Jun-Hong Wang

doi:10.1016/j.heliyon.2023.e14823

AGEs-RAGE-K_Ca3.1 pathway mediates palmitic acid-induced migration of PBMCs from patients with type 2 diabetes

Heliyon. 2023 Mar 24;9(4):e14823. doi: 10.1016/j.heliyon.2023.e14823. eCollection 2023 Apr.

Authors

Yi Zhang¹, Xiao-Zhen Ma¹, Xin-Yi Zhao¹, Jing-Jing Li¹, Shan Ma^{1

2}, Zheng-Da Pang¹, Jing Xu², Xiao-Jun Du¹, Xiu-Ling Deng¹, Jun-Hong Wang^{2

3}

Affiliations

¹ Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an, 710061, Shaanxi, China.
² Department of Endocrinology, The Second Affiliated Hospital, Xi'an Jiaotong University, 157 Fifth West Road, Xi'an, 710004, Shaanxi, China.
³ Department of Endocrinology, Gongli Hospital, Pudong New Area, Shanghai, 200135, China.

Abstract

Type 2 diabetes mellitus (T2DM) is characterized by chronic low-grade systemic inflammation. Tissue infiltration by monocyte migration contributes to the pathogenesis of vascular complications in T2DM. We studied the role of intermediate-conductance Ca²⁺-activated K⁺ (K_Ca3.1) channels in the palmitic acid (PA)-induced migration of peripheral blood mononuclear cells (PBMCs) from T2DM patients and the influence of advanced glycation endproducts (AGEs). A total of 49 T2DM patients and 33 healthy subjects was recruited into this study. Using flow cytometry and Western blotting analysis as well as cell migration assay, we found that there was a significant decrease in frequency of T lymphocytes and monocytes in CD45⁺ leukocyte population. PA at 100 μM stimulated migration of PBMCs from T2DM individuals, which was inhibited by the specific K_Ca3.1 channel blocker TRAM-34 (1 μM). The PBMC migration was positively correlated with glycosylated hemoglobin A1 chain (HbA1c) level of T2DM patients, an indicator of AGEs, and PBMCs with higher level of HbA1c showed upregulated expression of toll-like receptor (TLR) 2/4 and K_Ca3.1 channels. In THP-1 cells, AGEs at 200 μg/ml increased protein expression of TLR 2/4 and K_Ca3.1 channels, and were synergistically involved in PA-induced migration through receptors of AGEs (RAGE)-mediated K_Ca3.1 upregulation. In conclusion, in PBMCs of T2DM patients, AGEs promotes PA-induced migration via upregulation of TLR2/4 and K_Ca3.1 channels.

Keywords: HbA1c; Migration; Palmitic acid; Peripheral blood mononuclear cells; Type 2 diabetes mellitus.