Indoxyl Sulfate Dysregulates Choline Acetyltransferase-Mediated Cognitive Impairment in Patients with ESKD by Extrinsic Apoptosis in the Neuronal Cells during the Differentiating Process

Background: 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. Methods: A CKD animal model induced renal impairment in adenine-fed C57BL/6 mice, assessing memory loss and behavioral changes. Immunohistochemistry evaluated choline acetyltransferase. Differentiating SH-SY5Y cells were treated with IS to assessing cell viability. Reactive oxidized species generation was measured using DCFCA fluorescence. Results: 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. 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: IS levels was associated with cognitive impairment and neuronal apoptosis with choline transferase dysfunction. IS could be a therapeutic target for cognitive dysfunction in CKD.