Omega-3 Polyunsaturated Fatty Acid Attenuates Uremia-Induced Brain Damage in Mice.

Eun-Ji Kim,Dae Eun Choi,Jin Young Jeong,Ki Ryang Na,Kang Wook Lee,Young Rok Ham,Jin Ah Shin,Jwa-Jin Kim

doi:10.3390/ijms222111802

Eun-Ji Kim, Dae Eun Choi + Show 6 more

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https://doi.org/10.3390/ijms222111802

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Abstract

Although the cause of neurological disease in patients with chronic kidney disease (CKD) has not been completely identified yet, recent papers have identified accumulated uremic toxin as its main cause. Additionally, omega-3 polyunsaturated fatty acid (ω-3 PUFA) plays an important role in maintaining normal nerve function, but its protective effects against uremic toxin is unclear. The objective of this study was to identify brain damage caused by uremic toxicity and determine the protective effects of ω-3 PUFA against uremic toxin. We divided mice into the following groups: wild-type (wt) sham (n = 8), ω-3 PUFA sham (n = 8), Fat-1 sham (n = 8), ischemia-reperfusion (IR) (n = 20), and ω-3 PUFA+IR (n = 20) Fat-1+IR (n = 20). Brain tissue, kidney tissue, and blood were collected three days after the operation of mice (sham and IR operation). This study showed that Ki67 and neuronal nuclei (NeuN) decreased in the brain of uremic mice as compared to wt mice brain, but increased in the ω-3 PUFA-treated uremic mice and the brain of uremic Fat-1 mice as compared to the brain of uremic mice. The pro-apoptotic protein expressions were increased, whereas anti-apoptotic protein expression decreased in the brain of uremic mice as compared to wt mice brain. However, apoptotic protein expression decreased in the ω-3 PUFA-treated uremic mice and the brain of uremic Fat-1 mice as compared to the brain of uremic mice. Furthermore, the brain of ω-3 PUFA-treated uremic mice and uremic Fat-1 mice showed increased expression of p-PI3K, p-PDK1, and p-Akt as compared to the brain of uremic mice. We confirm that uremic toxin damages the brain and causes cell death. In these injuries, ω-3 PUFA plays an important role in neuroprotection through PI(3)K-Akt signaling.

Highlights

It is well known that multiple organs, including the brain, heart, lungs, and liver, are injured/affected progressively in patients with chronic kidney disease (CKD) [1,2]
eicosapentaenoic acid (EPA), a precursor to DHA, has been shown to exhibit neuroprotective effects by increasing the phosphorylation of Akt and inhibiting the activity of caspase-3 [13]. These findings suggested the neuroprotection of ω3-polyunsaturated fatty acids (PUFAs) through PI(3)K-Akt signaling in brain injury
Comparing blood tests after IR among wt, ω-3, and Fat-1, the levels of blood urea nitrogen (BUN) and serum creatinine (s-Cr) were significantly increased after IR injury compared to each control (Figure 1A)

Summary

Introduction

It is well known that multiple organs, including the brain, heart, lungs, and liver, are injured/affected progressively in patients with chronic kidney disease (CKD) [1,2] Various factors such as acid–base imbalance, volume overload, electrolyte derangement, and accumulation of uremic products cause these damages, uremic toxins are believed to play a major role in the progression of multiple organ damage [3,4]. Waste nitrogen products and various uremic toxins, including indoxyl sulfate, p-cresol, and hippuric acid, continue to accumulate in blood, thereby causing abnormally high levels. Most of these toxins damage organs and decrease their functions. Neuronal damage by uremic toxin has not been fully explained, and the underlying explanations for this observation are not clear

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