Indoxyl sulfate caused behavioral abnormality and neurodegeneration in mice with unilateral nephrectomy

Abstract

Chronic Kidney Disease (CKD) and neurodegenerative diseases are aging-related diseases. CKD with declined renal function is associated with an elevation of circulating indoxyl sulfate, a metabolite synthesized by gut microbes. We explored the roles of gut microbial metabolites in linking with Central Nervous System (CNS) diseases by administrating indoxyl sulfate intraperitoneally to male C57BL/6 mice with unilateral nephrectomy. Upon exposure, the accumulation of indoxyl sulfate was noted in the blood, prefrontal cortical tissues, and cerebrospinal fluid. Mice showed behavioral signs of mood disorders and neurodegeneration such as anxiety, depression, and cognitive impairment. Those behavioral changes were accompanied by disturbed neuronal survival, neural stem cell activity, expression of Brain-Derived Neurotrophic Factor, serotonin, corticosterone, and Repressor Element-1 Silencing Transcription Factor, and post-receptor intracellular signaling, as well as upregulated oxidative stress and neuroinflammation. Uremic toxin adsorbent AST-120 improved the above mentioned changes. Intriguingly, intracerebroventricular indoxyl sulfate administration only caused limited alterations in the normal mice and the alterations were reversed by aryl hydrocarbon receptor antagonism. The findings suggest pathogenic roles of indoxyl sulfate in the development of CNS diseases, and highlight gut microbiota as alternative targets for intervention with the aim of slowing down the progression of CKD and decreasing CNS complications.

Zebrafish Model-Based Assessment of Indoxyl Sulfate-Induced Oxidative Stress and Its Impact on Renal and Cardiac Development

“…Additionally, another study showed that injection of unilaterally nephrectomized mice with IS significantly increased the levels of the lipid peroxidation indicator malondialdehyde (MDA) in mouse urine and serum. Similarly, significantly decreased levels of antioxidants, including glutathione, SOD-1/SOD-2, and catalase, were detected [ 46 ], indicating that IS may induce oxidative stress by reducing endogenous antioxidant levels.…”

“…A study by Marzocco et al indicated that IS has proinflammatory effects on C57BL/6J mice and increases the expression of cox-2 and Bax [ 30 ]. Another study revealed that neuroinflammation [ 46 ], serum IL-1 protein levels, and prefrontal cortical tissue IL-1 mRNA levels are elevated in IS-treated mice. There is no direct evidence or data to allow the comparison of transcriptomic data between IS-treated zebrafish and uremic patients.…”

Uremic encephalopathy

“…These were linked to functional changes of neuronal cells and neuroinflammation. 39 Indoxyl sulfate also induced apoptosis of J o u r n a l P r e -p r o o f astrocytes via oxidative stress and protein kinase inhibition. 40 Indoxyl sulfate administration to rats with CKD impaired cognitive function and BBB integrity via aryl hydrocarbon receptor activation.…”

Uremic Toxins and Frailty in Patients with Chronic Kidney Disease: A Molecular Insight

“…In addition, chronically increased IS reduced neurotransmitters such as norepinephrine, serotonin, and dopamine in brainstem, increasing stress sensitivity and lowering locomotor activities, both of which were core characteristics of cognitive frailty [64]. There are also reports identifying IS in cerebrospinal fluids [65]. Nephrectomized mice receiving pCS for 7 weeks exhibit aberrant behavior suggesting cognitive impairment and neuropsychiatric disturbances [66].…”

“…IS entered central nervous system through the abnormal blood brain barrier with an increased permeability and induced neurobehavioral alterations through binding to the overexpressed AhR in cerebral tissues among CKD rats [67]. Exposure to IS also results in the suppression of neural stem cell activity and a lower level of brain-derived neurotrophic factors (BDNFs), amenable to correction by AhR antagonism [65].…”