p -Cresyl sulfate causes renal tubular cell damage by inducing oxidative stress by activation of NADPH oxidase

Abstract

The accumulation of p-cresyl sulfate (PCS), a uremic toxin, is associated with the mortality rate of chronic kidney disease patients; however, the biological functions and the mechanism of its action remain largely unknown. Here we determine whether PCS enhances the production of reactive oxygen species (ROS) in renal tubular cells resulting in cytotoxicity. PCS exhibited pro-oxidant properties in human tubular epithelial cells by enhancing NADPH oxidase (nicotinamide adenine dinucleotide phosphate-oxidase) activity. PCS also upregulated mRNA levels of inflammatory cytokines and active TGF-β1 protein secretion associated with renal fibrosis. Knockdown of p22(phox) or Nox4 expression suppressed the effect of PCS, underlining the importance of NADPH oxidase activation on its mechanism of action. PCS also reduced cell viability by increasing ROS production. The toxicity of PCS was largely suppressed in the presence of probenecid, an organic acid transport inhibitor. Administration of PCS for 4 weeks caused significant renal tubular damage in 5/6-nephrectomized rats by enhancing oxidative stress. Thus, the renal toxicity of PCS is attributed to its intracellular accumulation, leading to both increased NADPH oxidase activity and ROS production, which, in turn, triggers induction of inflammatory cytokines involved in renal fibrosis. This mechanism is similar to that for the renal toxicity of indoxyl sulfate.

Potential therapeutic interventions for chronic kidney disease‐associated sarcopenia via indoxyl sulfate‐induced mitochondrial dysfunction

“…sea:ICR mice (5 weeks, male) were purchased from Kudo Co., Ltd (Saga, Japan) and bred on a 12 h day/night cycle. 5/6‐nephrectomized model mice were produced in a two‐step surgery procedure according to previous reports 15. In brief, two‐thirds of the right kidney was removed, and 1 week later, the left kidney was removed.…”

Inflammation is associated to volume status in peritoneal dialysis patients

“…27 Animal models have demonstrated that uremic toxins such as p-cresyl sulfate (PCS) and indoxyl sulfate (IS) induce proinflammatory cytokine production. 28,29 In addition, recently, Rossi et al 30 have demonstrated that IS and PCS levels were associated with elevated levels of selected inflammatory markers and an antioxidant in 149 predialysis patients with a mean eGFR of 40 ± 9 mL/min/1.73 m 2 . Similarly, we found that there was an association between inflammation and residual renal functions.…”

Aryl Hydrocarbon Receptor Mediates Indoxyl Sulfate-Induced Cellular Senescence in Human Umbilical Vein Endothelial Cells

“…Therefore, Sirt1 is considered to be a key player in the promotion of oxidative stress-mediated cellular senescence 23) . Uremic toxins, accumulate in association with the progression of renal dysfunction, have been demonstrated to augment oxidative stress in CKD patients 9, [24][25][26] . Indoxyl sulfate (IS), a protein-bound uremic toxin, is metabolized in the liver by tryptophan-derived indole, which is produced by tryptophanase in intestinal bacteria and normally excreted into the urine 27) .…”