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Chronic kidney disease alters lipid trafficking and inflammatory responses in macrophages: effects of liver X receptor agonism

2018; BioMed Central; Volume: 19; Issue: 1 Linguagem: Inglês

10.1186/s12882-018-0814-8

1471-2369

Ryohei Kaseda, Yohei Tsuchida, Hai-Chun Yang, Patricia G. Yancey, Jianyong Zhong, Tao Huan, Aihua Bian, Agnes B. Fogo, Mac Rae F. Linton, Sergio Fazio, T. Alp İkizler, Valentina Kon,

Liver Disease Diagnosis and Treatment

Background: Our aim was to evaluate lipid trafficking and inflammatory response of macrophages exposed to lipoproteins from subjects with moderate to severe chronic kidney disease (CKD), and to investigate the potential benefits of activating cellular cholesterol transporters via liver X receptor (LXR) agonism.Methods: LDL and HDL were isolated by sequential density gradient ultracentrifugation of plasma from patients with stage 3-4 CKD and individuals without kidney disease (HDL CKD and HDL Cont , respectively).Uptake of LDL, cholesterol efflux to HDL, and cellular inflammatory responses were assessed in human THP-1 cells.HDL effects on inflammatory markers (MCP-1, TNF-α, IL-1β), Toll-like receptors-2 (TLR-2) and -4 (TLR-4), ATP-binding cassette class A transporter (ABCA1), NF-κB, extracellular signal regulated protein kinases 1/2 (ERK1/2) were assessed by RT-PCR and western blot before and after in vitro treatment with an LXR agonist.Results: There was no difference in macrophage uptake of LDL isolated from CKD versus controls.By contrast, HD CKD was significantly less effective than HDL Cont in accepting cholesterol from cholesterol-enriched macrophages (median 20.8% ] vs control (26.5% ]; p = 0.008).LXR agonist upregulated ABCA1 expression and increased cholesterol efflux to HDL of both normal and CKD subjects, although the latter continued to show lower efflux capacity.HDL CKD increased macrophage cytokine response (TNF-α, MCP-1, IL-1β, and NF-κB) versus HDL Cont .The heightened cytokine response to HDL CKD was further amplified in cells treated with LXR agonist.The LXR-augmentation of inflammation was associated with increased TLR-2 and TLR-4 and ERK1/2.Conclusions: Moderate to severe impairment in kidney function promotes foam cell formation that reflects impairment in cholesterol acceptor function of HDL CKD .Activation of cellular cholesterol transporters by LXR agonism improves but does not normalize efflux to HDL CKD .However, LXR agonism actually increases the pro-inflammatory effects of HDL CKD through activation of TLRs and ERK1/2 pathways.