The AST-120 Recovers Uremic Toxin-Induced Cognitive Deficit via NLRP3 Inflammasome Pathway in Astrocytes and Microglia.

Chiang-Chi Huang,Jin-Bor Chen,Lung-Chih Li,Hong-Tai Tzeng,Ya-Jen Chang,Wei-Yu Chen,Chiung-Chih Chang,Jenq-Lin Yang,Wen-Chin Lee

doi:10.3390/biomedicines9091252

Abstract

Chronic kidney disease (CKD) is characterized by the progressive loss of renal function; moreover, CKD progression commonly leads to multiple comorbidities, including neurological dysfunction and immune disorders. CKD-triggered neuroinflammation significantly contributes to cognitive impairment. This study aimed to investigate the contribution of uremic toxins to cognitive impairment. Serum creatinine, blood urea nitrogen (BUN), indoxyl sulfate (IS), and p-cresol sulfate (PCS) levels were measured using an enzyme-linked immunosorbent assay and high-performance liquid chromatography. The creatinine, BUN, IS, and PCS levels were increased from 4 weeks after 5/6-nephrectomy in mice, which suggested that 5/6-nephrectomy could yield a CKD animal model. Further, CKD mice showed significantly increased brain and serum indoxyl sulfate levels. Immunohistochemistry analysis revealed hippocampal inflammation and NLRP3-inflammasomes in astrocytes. Further, the Y-maze and Morris water maze tests revealed learning and memory defects in CKD mice. AST-120, which is also an IS absorbent, effectively reduced serum and hippocampal IS levels as well as reversed the cognitive impairment in CKD mice. Additionally, NLRP3-knockout mice that underwent 5/6-nephrectomy showed no change in cognitive function. These findings suggested that IS is an important uremic toxin that induces NLRP3 inflammasome-mediated not only in microglia, but it also occurred in astrocytic inflammation, which subsequently causes cognitive impairment.

Highlights

Chronic kidney disease (CKD) is characterized by the gradual and progressive loss of kidney function over months or years
The mechanisms underlying the contribution of each uremic toxin to the central nervous system (CNS) and cognitive impairment remain unclear [10,23]
The p-cresol sulfate (PCS) levels were significantly increased only in the hippocampus (Figure 3B). These findings suggest that the hippocampus is the most vulnerable brain region to uremic toxins; we focused on this brain region

Summary

Introduction

Chronic kidney disease (CKD) is characterized by the gradual and progressive loss of kidney function over months or years. CKD can be caused by diabetes, hypertension, cardiovascular heart diseases, glomerulonephritis, polycystic kidney disease, and aging. The prevalence of CKD is an important public health issue since it has resulted in a heavy burden on health care systems worldwide [1]. Patients with CKD commonly present with multiple comorbidities, including neurological disorders [2], anemia [3], cardiomyopathy and hypertension [4], secondary hyperparathyroidism [5], and immune disorders [6]. Cognitive impairment often occurs in all CKD stages, including end-stage renal disease; it affects daily life, as well as results in a higher mortality rate and longer hospitalization [7]. The prevalence of cognitive impairment in patients with CKD has been

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