Abstract
Protein-bound uremic toxins, such as p-cresol sulfate (PCS), can be accumulated with declined renal function and aging and is closely linked with central nervous system (CNS) diseases. In the periphery, PCS has effects on oxidative stress and inflammation. Since oxidative stress and inflammation have substantial roles in the pathogenesis of neurological disorders, the CNS effects of PCS were investigated in unilateral nephrectomized C57/BL/6 mice. Unlike intact mice, unilateral nephrectomized mice showed increased circulating levels of PCS after exogenous administration. Upon PCS exposure, the unilateral nephrectomized mice developed depression-like, anxiety-like, and cognitive impairment behaviors with brain PCS accumulation in comparison with the nephrectomy-only group. In the prefrontal cortical tissues, neuronal cell survival and neurogenesis were impaired along with increased apoptosis, oxidative stress, and neuroinflammation. Circulating brain-derived neurotrophic factors (BDNF) and serotonin were decreased in association with increased corticosterone and repressor element-1 silencing transcription factor (REST), regulators involved in neurological disorders. On the contrary, these PCS-induced changes were alleviated by uremic toxin absorbent AST-120. Taken together, PCS administration in mice with nephrectomy contributed to neurological disorders with increased oxidative stress and neuroinflammation, which were alleviated by PCS chelation. It is suggested that PCS may be a therapeutic target for chronic kidney disease-associated CNS diseases.
Highlights
The incidence and prevalence of chronic kidney disease (CKD) are increasing rapidly worldwide [1]
Oxidative stress has an impact on neural function and the overwhelmed oxidative stress contributes to the pathogenesis of central nervous system (CNS) diseases [29,30,31,32,33]
CKD has been well associated with several CNS diseases [2,3,4]
Summary
The incidence and prevalence of chronic kidney disease (CKD) are increasing rapidly worldwide [1]. In a 5/6 nephrectomy CKD rodent model, the content of PCS is elevated in systemic circulation and the brain tissues, while the increments are decreased by uremic toxin absorbent AST-120 [9,11]. Treatment with PCS increased its presence in the serum (Figure 3A) and prefrontal cortical tissues (Figure 3B), while the increments were alleviated by uremic toxin absorbent AST-120 (Figure 3). AST-120 alleviated the protein reduction and caspase 3 activation in PCS mice (Figure 5). These findings indicate that PCS had a negative effects on neuronal cells and neural stem cells, as well as promoted cell apoptosis, while the alterations can be alleviated bInyt. PCS exposure decreased the glutathione (GSH) content (Figure 7D), increased the 8-hydroxy-2-deoxyguanosine (8-OH-dG) content (Figure 7E) and NADPH oxidase-4 (NOX4) (Figure 7F,G), and lowered the NF-E2-related factor (Nrf2), heme oxygenase-1
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