The accumulation of the uremic toxin
indoxyl sulfate (IS) is a key pathological feature of
chronic kidney disease (CKD). The effect of IS on ferroptosis and the role of IS-related ferroptosis in CKD are not well understood. We used a renal tubular cell model and an
adenine-induced CKD mouse model to explore whether IS induces ferroptosis and injury and affects
iron metabolism in the renal cells and the kidneys. Our results showed that exposure to IS induced several characteristics for ferroptosis, including
iron accumulation, an impaired
antioxidant system, elevated
reactive oxygen species (ROS) levels, and lipid peroxidation. Exposure to IS triggered intracellular
iron accumulation by upregulating
transferrin and
transferrin receptors, which are involved in cellular
iron uptake. We also observed increased levels of the
iron storage
protein ferritin. The effects of IS-induced ROS generation, lipid peroxidation, ferroptosis, senescence, ER stress, and injury/
fibrosis were effectively alleviated by treatments with an
iron chelator deferoxamine (DFO) in vitro and the adsorbent
charcoal AST-120 (scavenging the IS precursor) in vivo. Our findings suggest that IS triggers intracellular
iron accumulation and ROS generation, leading to the induction of ferroptosis, senescence, ER stress, and injury/
fibrosis in CKD kidneys.
AST-120 administration may serve as a potential therapeutic strategy.