Abstract
In chronic kidney disease (CKD) patients, accumulation of uremic toxins is associated with cardiovascular risk and mortality. One of the hallmarks of kidney disease-related cardiovascular disease is intravascular macrophage inflammation, but the mechanism of the reaction with these toxins is not completely understood. Macrophages differentiated from THP-1 cells were exposed to indoxyl sulfate (IS), a representative uremic toxin, and changes in inflammatory cytokine production and intracellular signaling molecules including interleukin (IL)-1, aryl hydrocarbon receptor (AhR), nuclear factor (NF)-κ, and mitogen-activated protein kinase (MAPK) cascades as well as the NLRP3 inflammasome were quantified by real-time PCR, Western blot analysis, and enzyme-linked immunosorbent assay. IS induced macrophage pro-IL-1β mRNA expression, although mature IL-1 was only slightly increased. IS increased AhR and the AhR-related mRNA expression; this change was suppressed by administration of proteasome inhibitor. IS promoted phosphorylation of NF-κB p65 and MAPK enzymes; the reaction and IL-1 expression were inhibited by BAY11-7082, an inhibitor of NF-κB. In contrast, IS decreased NLRP3 and did not change ASC, pro-caspase 1, or caspase-1 activation. IS-inducing inflammation in macrophages results from accelerating AhR-NF-κB/MAPK cascades, but the NLRP3 inflammasome was not activated. These reactions may restrict mature IL-1β production, which may explain sustained chronic inflammation in CKD patients.
Highlights
Chronic kidney disease (CKD) patients have a higher mortality risk than the general population, and is related to a higher incidence of cardiovascular disease (CVD) [1]
We examined the roles of aryl hydrocarbon receptor (AhR)/nuclear factor (NF)-κB/mitogen-activated protein kinase (MAPK) and the NLRP3 inflammasome in macrophages reacted with indoxyl sulfate (IS) in vitro
The increase in pro-IL-1 expression appeared to be more obvious than the increase in mature IL-1 production when compared to the reaction with lipopolysaccharide (LPS, 100 ng/mL) in macrophages
Summary
Chronic kidney disease (CKD) patients have a higher mortality risk than the general population, and is related to a higher incidence of cardiovascular disease (CVD) [1]. Accumulation of protein-bound uremic toxins (PBUTs) in atherosclerotic lesions is an important factor in CKD-related CVD. PBUTs are increased as kidney function deteriorates and are difficult to eliminate by conventional dialysis treatments because of their protein-binding abilities [3]. The serum level of indoxyl sulfate (IS), a representative PBUT, increases with. CKD progression, and a high serum IS level is associated with a higher incidence of cardiovascular mortality [4]. Kidney damage accelerated atherosclerosis with increased IS deposition and inflammatory cytokine expression in the lesions; reduction of IS deposition in the lesion with oral charcoal adsorbent inhibited the acceleration of atherosclerosis [5]. IS may directly react with cells within atherosclerotic lesions
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