Indoxyl sulfate (IS) is a
protein-bound uremic toxin resulting from the metabolism of dietary
tryptophan which accumulates in patients with impaired renal function, such as
chronic kidney disease (CKD). IS is a well-known nephrovascular toxin but little is known about its effects on central nervous system (CNS) cells. Considering the growing interest in the field of CNS comorbidities in CKD, we studied the effect of IS on CNS cells. IS (15-60 μM) treatment in C6 astrocyte cells increased
reactive oxygen species release and decreased nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activation, and
heme oxygenase-1 (HO-1) and
NAD(P)H dehydrogenase quinone 1 expression. Moreover, IS increased
Aryl hydrocarbon Receptor (AhR) and Nuclear Factor-kB (
NF-kB) activation in these cells. Similiar observations were made in primary mouse astrocytes and mixed glial cells.
Inducible nitric oxide synthase and
cyclooxygenase-2 (COX-2) expression,
tumor necrosis factor-α and
interleukin-6 release and
nitrotyrosine formation were increased by IS (15-60 μM) in primary mouse astrocytes and mixed glial cells. IS increased AhR and
NF-kB nuclear translocation and reduced Nrf2 translocation and HO-1 expression in primary glial cells. In addition, IS induced cell death in neurons in a dose dependent fashion. Injection of IS (800 mg/kg, i.p.) into mice induced histological changes and increased COX-2 expression and
nitrotyrosine formation in thebrain tissue. Taken together, our results show a significant contribution of IS in generating a neurotoxic enviroment and it could also have a potential role in neurodegeneration. IS could be considered also a potential therapeutical target for CKD-associated neurodegenerative complications.