Indoxyl Sulfate, a Tubular Toxin, Contributes to the Development of Chronic Kidney Disease

Abstract

Indoxyl sulfate (IS), a uremic toxin, causes chronic kidney disease (CKD) progression via its tubulotoxicity. After cellular uptake, IS directly induces apoptotic and necrotic cell death of tubular cells. Additionally, IS increases oxidative stress and decreases antioxidant capacity, which are associated with tubulointerstitial injury. Injured tubular cells are a major source of transforming growth factor-β1 (TGF-β1), which induces myofibroblast transition from residual renal cells in damaged kidney, recruits inflammatory cells and thereby promotes extracellular matrix deposition in renal fibrosis. Moreover, IS upregulates signal transducers and activators of transcription 3 phosphorylation, followed by increases in TGF-β1, monocyte chemotactic protein-1 and α-smooth muscle actin production, which participate in interstitial inflammation, renal fibrosis and, consequently, CKD progression. Clinically, higher serum IS levels are independently associated with renal function decline and predict all-cause mortality in CKD. The poor removal of serum IS in conventional hemodialysis is also significantly associated with all-cause mortality and heart failure incidence in end-stage renal disease patients. Scavenging the IS precursor by AST-120 can markedly reduce tubular IS staining that attenuates renal tubular injury, ameliorates IS-induced oxidative stress and rescues antioxidant glutathione activity in tubular epithelial cells, thereby providing a protective role against tubular injury and ultimately retarding renal function decline.

Protein-Bound Uremic Toxins Induce Reactive Oxygen Species-Dependent and Inflammasome-Mediated IL-1β Production in Kidney Proximal Tubule Cells

“…Proximal tubular cells are specialized in the uptake and excretion of IS thanks to the abundant expression of transporters of the organic anion pathway, and therefore can be more susceptible to their biological effects compared to other cell types [30,59,60]. In fact, IS is directly cytotoxic to renal tubules and is considered as one of the most important toxins contributing to CKD progression [61]. The oxidative stress induced by IS, associated with a production of a plethora of pro-inflammatory and pro-fibrotic factors, is one of the key players of IS-mediated cytotoxicity of tubular cells [31,61].…”

“…In fact, IS is directly cytotoxic to renal tubules and is considered as one of the most important toxins contributing to CKD progression [61]. The oxidative stress induced by IS, associated with a production of a plethora of pro-inflammatory and pro-fibrotic factors, is one of the key players of IS-mediated cytotoxicity of tubular cells [31,61]. Therefore, the contrasting observations on how IS influences NLRP3 inflammasome activation and the lack of To our knowledge, we showed for the first time that IS (and the PBUTs mixture) induced NLRP3 expression both at mRNA and protein levels in proximal tubule cells, accompanied by increased caspase-1 activity and IL-1β expression and secretion.…”

“…In fact, IS is directly cytotoxic to renal tubules and is considered as one of the most important toxins contributing to CKD progression [61]. The oxidative stress induced by IS, associated with a production of a plethora of proinflammatory and pro-fibrotic factors, is one of the key players of IS-mediated cytotoxicity of tubular cells [31,61]. Therefore, the contrasting observations on how IS influences NLRP3 inflammasome activation and the lack of relevant studies suggest that further research implementing different cell types and animal models is required to better understand the role of PBUTs in inflammasome regulation in specific tissues and organs.…”

Predictive and Preventive Mucosal Communications in Particulate Matter Exposure-Linked Renal Distress

“…In addition to effects on ROS production and xenobiotic metabolism, AhR-linked signaling is involved in proinflammatory cytokine production and cell death responses [ 70 , 71 ]. URS-induced oxidative stress and proinflammatory cytokines cause necrotic and apoptotic death of the renal tubular and renovascular cells [ 72 , 73 ]. Mechanistically, PM- or URS-activated AhR can disrupt the mitochondrial membrane potential or trigger other diverse cell death signaling pathways, which is the crucial step of renal tubular and renovascular tissue injuries during PM exposure [ 72 , 73 , 74 , 75 ].…”

“…URS-induced oxidative stress and proinflammatory cytokines cause necrotic and apoptotic death of the renal tubular and renovascular cells [ 72 , 73 ]. Mechanistically, PM- or URS-activated AhR can disrupt the mitochondrial membrane potential or trigger other diverse cell death signaling pathways, which is the crucial step of renal tubular and renovascular tissue injuries during PM exposure [ 72 , 73 , 74 , 75 ]. In contrast, PM, URS, and their active metabolites attenuate the antioxidant capacity in response to the oxidative stress in the mucosa-renal axis.…”