Indoxyl sulfate is associated with cognitive impairment in ESRD patients by activating the extrinsic apoptosis in the neuronal cells during differentiating process.

Aim: This study investigates the correlation between indoxyl sulfate (IS) levels and cognitive impairment in end-stage renal disease (ESRD) patients from human study, in vivo and in vitro study. Materials and Methods: Comparison of demographic and biochemical data, including IS concentrations, was conducted between a control group(n=16) and the ESRD with cognitive impairment group (n=14) and without cognitive impairment (n=17). A CKD animal model induced renal impairment in adenine-fed C57BL/6 mice, assessing memory loss and behavioral changes. Immunohistochemistry evaluated choline acetyltransferase activity and GFAP expression. Differentiating SH-SY5Y cells were treated with IS, assessing cell viability and apoptosis via annexin V and propidium iodide staining and western blotting. Reactive oxidized species generation was measured using DCFCA fluorescence and NAC pretreatment. Results: In ESRD patients with cognitive impairment, IS levels were significantly higher compared to healthy controls, along with older age. CKD mice exhibited renal impairment and memory loss, accompanied by altered choline acetyltransferase activity and GFAP expression. IS treatment induced early apoptosis in SH-SY5Y cells, associated with increased cleaved caspase 3 levels and Fas/Fas-ligand activity, altered Bax/Bcl2 ratio, and reactive oxidized species generation. Conclusion: Elevated IS levels are associated with cognitive impairment and neuronal apoptosis, potentially mediated by oxidative stress. IS could be a therapeutic target for cognitive dysfunction in CKD, necessitating further research into its mechanisms and therapeutic interventions.