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Toxins 2015, 7(8), 3155-3166; doi:10.3390/toxins7083155

Increased Proinflammatory Cytokine Production and Decreased Cholesterol Efflux Due to Downregulation of ABCG1 in Macrophages Exposed to Indoxyl Sulfate

Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
Division of Blood Purification Therapy, Niigata University Medical and Dental Hospital, Niigata 951-8520, Japan
Author to whom correspondence should be addressed.
Academic Editor: R. Vanholder
Received: 6 July 2015 / Revised: 31 July 2015 / Accepted: 6 August 2015 / Published: 14 August 2015
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One of the possible causes of enhanced atherosclerosis in patients with chronic kidney disease (CKD) is the accumulation of uremic toxins. Since macrophage foam cell formation is a hallmark of atherosclerosis, we examined the direct effect of indoxyl sulfate (IS), a representative uremic toxin, on macrophage function. Macrophages differentiated from THP-1 cells were exposed to IS in vitro. IS decreased the cell viability of THP-1 derived macrophages but promoted the production of inflammatory cytokines (IL-1β, IS 1.0 mM: 101.8 ± 21.8 pg/mL vs. 0 mM: 7.0 ± 0.3 pg/mL, TNF-α, IS 1.0 mM: 96.6 ± 11.0 pg/mL vs. 0 mM: 15.1 ± 3.1 pg/mL) and reactive oxygen species. IS reduced macrophage cholesterol efflux (IS 0.5 mM: 30.3% ± 7.3% vs. 0 mM: 43.5% ± 1.6%) and decreased ATP-binding cassette transporter G1 expression. However, lipid uptake into cells was not enhanced. A liver X receptor (LXR) agonist, T0901317, improved IS-induced production of inflammatory cytokines as well as reduced cholesterol efflux. In conclusion, IS induced inflammatory reactions and reduced cholesterol efflux in macrophages. Both effects of IS were improved with activation of LXR. Direct interactions of uremic toxins with macrophages may be a major cause of atherosclerosis acceleration in patients with CKD. View Full-Text
Keywords: indoxyl sulfate; macrophage; chronic kidney disease; atherosclerosis indoxyl sulfate; macrophage; chronic kidney disease; atherosclerosis

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Matsuo, K.; Yamamoto, S.; Wakamatsu, T.; Takahashi, Y.; Kawamura, K.; Kaneko, Y.; Goto, S.; Kazama, J.J.; Narita, I. Increased Proinflammatory Cytokine Production and Decreased Cholesterol Efflux Due to Downregulation of ABCG1 in Macrophages Exposed to Indoxyl Sulfate. Toxins 2015, 7, 3155-3166.

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