Uremic Toxin Indoxyl Sulfate Promotes Macrophage-Associated Low-Grade Inflammation and Epithelial Cell Senescence

Abstract

In this study, we investigated the impact of the uremic toxin indoxyl sulfate on macrophages and tubular epithelial cells and its role in modulating the response to lipopolysaccharide (LPS). Indoxyl sulfate accumulates in the blood of patients with chronic kidney disease (CKD) and is a predictor of overall and cardiovascular morbidity/mortality. To simulate the uremic condition, primary macrophages and tubular epithelial cells were incubated with indoxyl sulfate at low concentrations as well as concentrations found in uremic patients, both alone and upon LPS challenge. The results showed that indoxyl sulfate alone induced the release of reactive oxygen species and low-grade inflammation in macrophages. Moreover, combined with LPS (proinflammatory conditions), indoxyl sulfate significantly increased TNF-α, CCL2, and IL-10 release but did not significantly affect the polarization of macrophages. Pre-treatment with indoxyl sulfate following LPS challenge induced the expression of aryl hydrocarbon receptor (Ahr) and NADPH oxidase 4 (Nox4) which generate reactive oxygen species (ROS). Further, experiments with tubular epithelial cells revealed that indoxyl sulfate might induce senescence in parenchymal cells and therefore participate in the progression of inflammaging. In conclusion, this study provides evidence that indoxyl sulfate provokes low-grade inflammation, modulates macrophage function, and enhances the inflammatory response associated with LPS. Finally, indoxyl sulfate signaling contributes to the senescence of tubular epithelial cells during injury.

Systemic impacts of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) on heart, muscle, and kidney related diseases

“…Elevated IS levels induce oxidative stress and inflammation in renal tubular cells, promoting fibrosis and accelerating the decline in renal function ( Barreto et al, 2009 ). Moreover, IS was also found to be increased in MASLD patients ( Hotamisligil, 2006 ; Ribeiro et al, 2023 ). Mechanistically, IS activates the aryl hydrocarbon receptor (AhR) pathway and induces the expression of TGF-β and pro-inflammatory cytokines, thereby exacerbating renal injury ( Delgado-Marin et al, 2024 ).…”

An Overview of Chronic Kidney Disease Pathophysiology: The Impact of Gut Dysbiosis and Oral Disease

“…Accumulation of toxins and proinflammatory cytokines may constitute DAMPs to which endothelial cells are continuously exposed. In parallel, the increase in toxic substances provokes immunodeficiency in CKD patients, leading to a suppression of humoral and immune responses [76]. Multiple studies demonstrated that the accumulation of GDUTs leads to the occurrence and development of CKD and increases the risk of cardiovascular events in CKD [24,[77][78][79][80].…”