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BMC Nephrology
Published in: BMC Nephrology 1/2018

Open Access 01-12-2018 | Research article

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

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

Published in: BMC Nephrology | Issue 1/2018

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Abstract

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 (HDLCKD and HDLCont, 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, HDCKD was significantly less effective than HDLCont in accepting cholesterol from cholesterol-enriched macrophages (median 20.8% [IQR 16.1–23.7] vs control (26.5% [IQR 19.6–28.5]; 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. HDLCKD increased macrophage cytokine response (TNF-α, MCP-1, IL-1β, and NF-κB) versus HDLCont. The heightened cytokine response to HDLCKD 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 HDLCKD. Activation of cellular cholesterol transporters by LXR agonism improves but does not normalize efflux to HDLCKD. However, LXR agonism actually increases the pro-inflammatory effects of HDLCKD through activation of TLRs and ERK1/2 pathways.
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Metadata
Title
Chronic kidney disease alters lipid trafficking and inflammatory responses in macrophages: effects of liver X receptor agonism
Authors
Ryohei Kaseda
Yohei Tsuchida
Hai-Chun Yang
Patricia G. Yancey
Jianyong Zhong
Huan Tao
Aihua Bian
Agnes B. Fogo
Mac Rae F. Linton
Sergio Fazio
Talat Alp Ikizler
Valentina Kon
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Nephrology / Issue 1/2018
Electronic ISSN: 1471-2369
DOI
https://doi.org/10.1186/s12882-018-0814-8

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