Effect of uremic toxins on hippocampal cell damage: analysis in vitro and in rat model of chronic kidney disease

Kimio Watanabe,Emiko Sato,Eikan Mishima,Mayu Watanabe,Takaaki Abe,Nobuyuki Takahashi,Masaaki Nakayama

doi:10.1016/j.heliyon.2021.e06221

Kimio Watanabe, Emiko Sato + Show 5 more

Open Access

https://doi.org/10.1016/j.heliyon.2021.e06221

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Abstract

One third of the patients with chronic kidney disease (CKD) develop cognitive impairment, which is also an independent risk factor for mortality. However, the concise mechanism of cerebro-renal interaction has not been clarified. The present study examines the effects of uremic toxins on neuronal cells and analyzes the pathological condition of the brain using mouse hippocampal neuronal HT-22 cells and adenine-induced CKD model rats. Among the uremic toxins analyzed, indoxyl sulfate, indole, 3-indoleacetate, and methylglyoxal significantly decreased viability and glutathione level in HT-22 cells. The mixture of these uremic toxins also decreased viability and glutathione level at a lower dose. Adenine-induced CKD rat showed marked renal damage, increased urinary oxidative stress markers, and increased numbers of pyknotic neuronal cells in hippocampus. CKD rats with damaged hippocampus demonstrated poor learning process when tested using the Morris water maze test. Our results suggest that uremic toxins have a toxic effect on hippocampal neuronal cells and uremic CKD rats shows pyknosis in hippocampus.

Highlights

Cognitive impairment is commonly seen among patients with chronic kidney disease (CKD), with a prevalence of 16%–38% [1, 2, 3]
We examined the effects of uremic toxins on the neuronal cells and pathological condition of the brain using the mouse hippocampal neuronal cell line, HT-22 and adenine-induced CKD rats, which is widely
We examined the expression of nuclear factor (erythroid-2-related factor)-2 (Nrf2), which is a main transcription activator in response to oxidative stress [23], stimulated by 50 μM indoxyl sulfate in HT-22 cells

Summary

Introduction

Cognitive impairment is commonly seen among patients with chronic kidney disease (CKD), with a prevalence of 16%–38% [1, 2, 3]. Cognitive impairment has been associated with increased mortality in CKD [7]. In CKD, a number of harmful solutes retain in blood and tissues, which are called uremic toxins. Retention of uremic toxins is involved in a variety of symptoms such as vascular calcification, renal anemia, and osteoporosis, all of which appear in CKD patients. Retention of uremic toxins is considered as a risk factor for cognitive impairment in CKD [8, 9]. Direct neuronal injury by uremic toxins could be involved in the cognitive impairment in CKD. We examined the effects of uremic toxins on the neuronal cells and pathological condition of the brain using the mouse hippocampal neuronal cell line, HT-22 and adenine-induced CKD rats, which is widely used as an animal model of CKD showing obvious elevation of uremic toxins levels and kidney function impairment [12, 13, 14]

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