Increased Proinflammatory Cytokine Production and Decreased Cholesterol Efflux Due to Downregulation of ABCG1 in Macrophages Exposed to Indoxyl Sulfate.
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.
Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan. ko.matsu.notre@gmail.com.
Koji
K
Matsuo
Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan. yamamots@med.niigata-u.ac.jp.
Suguru
S
Yamamoto
Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan. tkywakamatsu@yahoo.co.jp.
Takuya
T
Wakamatsu
Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan. yoshimitsu2003@gmail.com.
Yoshimitsu
Y
Takahashi
Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan. kazukawamura@hotmail.com.
Kazuko
K
Kawamura
Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan. kanekoy@med.niigata-u.ac.jp.
Yoshikatsu
Y
Kaneko
Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan. gotos@med.niigata-u.ac.jp.
Shin
S
Goto
Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan. jjkaz@med.niigata-u.ac.jp.|Division of Blood Purification Therapy, Niigata University Medical and Dental Hospital, Niigata 951-8520, Japan. jjkaz@med.niigata-u.ac.jp.
Junichiro J
JJ
Kazama
Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan. naritai@med.niigta-u.ac.jp.
Ichiei
I
Narita
D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D050197:Atherosclerosis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D007200:Indican / Q000494:pharmacology*; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000819:agonists; D017382:Reactive Oxygen Species / Q000378:metabolism; D051436:Renal Insufficiency, Chronic; D013449:Sulfonamides / Q000494:pharmacology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D002784:Cholesterol; D016207:Cytokines; D006845:Hydrocarbons, Fluorinated; D007200:Indican; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D017382:Reactive Oxygen Species; D013449:Sulfonamides; C419353:ABCG1 protein, human; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
atherosclerosis; chronic kidney disease; indoxyl sulfate; macrophage