Abstract
Chronic kidney disease (CKD) involves multiple organ dysfunction, and the neurological complications that are often present in CKD patients support the idea of a crosstalk between the kidneys and the brain. Evidence suggests a possible role for products accumulating in these patients as uremic toxins in various CKD complications, including neurodegeneration. Indoxyl sulfate (IS), derived from tryptophan metabolism, is well-known as a uremic nephron-vascular toxin, and recent evidence suggests it also has a role in the immune response and in neurodegeneration. Inflammation has been associated with neurodegenerative diseases, as well as with CKD. In this study, we demonstrated that sera of CKD patients induced a significant inflammation in astrocyte cells which was proportional to IS sera concentrations, and that the IS adsorbent, AST-120, reduced this inflammatory response. These results indicated that, among the uremic toxins accumulating in serum of CKD patients, IS significantly contributed to astrocyte inflammation. Moreover, being also chronic inflammation associated with CKD, here we reported that IS further increased inflammation and oxidative stress in primary central nervous system (CNS) cells, via Nuclear Factor-κB (NF-κB) and Aryl hydrocarbon Receptor (AhR) activation, and induced neuron death. This study is a step towards elucidating IS as a potential pharmacological target in CKD patients.
Highlights
Neurodegenerative diseases are a heterogeneous group of chronic and progressive disorders which are characterized by a gradual loss of anatomically and/or physiologically related neuronal systems
Our results indicated that Reactive oxygen species (ROS) release was not significantly influenced in C6 cells treated with sera of human healthy people (H1–H4; Figure 1A), but resulted increased in the cells treated with sera of chronic kidney disease (CKD) patients (CKD1–CKD8; Figure 1B), and mostly in the cells treated with CKD dialysed patients serum (HD1–HD6; Figure 1C), both in normal (Figure 1A–C), and in inflammatory conditions (Figure 1E–G)
In order to evaluate the specific contribution of Indoxyl sulfate (IS) among all the uremic toxins accumulating in CKD serum, an IS-adsorbent AST-120 was used in some experiments
Summary
Neurodegenerative diseases are a heterogeneous group of chronic and progressive disorders which are characterized by a gradual loss of anatomically and/or physiologically related neuronal systems. This phenomenon, which mainly affects elderly individuals [1,2], occurs in neurodegenerative diseases, such as Alzheimer’s disease, multiple sclerosis and Parkinson’s disease [3]. Neurodegenerative disorders have been associated with chronic kidney disease (CKD). CKD is frequently associated with cognitive impairments, and it has been estimated that more than 85% of hemodialyzed (HD) patients with terminal CKD have cognitive deficits [7,8,9,10]. The neurological disease in CKD includes symptoms of cognitive slowing, attention deficits, reduced cognitive flexibility, interference susceptibility, verbal and non-verbal memory deficits, language deficits, dementia, and encephalopathy [11]
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