TUDCA-Treated Mesenchymal Stem Cells Protect against ER Stress in the Hippocampus of a Murine Chronic Kidney Disease Model.

Jun Lee,Yeo Yoon,Sang Lee

doi:10.3390/ijms20030613

Abstract

Chronic kidney disease (CKD) leads to the loss of kidney function, as well as the dysfunction of several other organs due to the release of uremic toxins into the system. In a murine CKD model, reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress are increased in the hippocampus. Mesenchymal stem cells (MSCs) are one of the candidates for cell-based therapy for CKD; however severe pathophysiological conditions can decrease their therapeutic potential. To address these issues, we established tauroursodeoxycholic acid (TUDCA)-treated MSCs using MSCs isolated from patients with CKD (CKD-hMSCs) and assessed the survival and ROS generation of neural cell line SH-SY5Y cells by co-culturing with TUDCA-treated CKD-hMSCs. In the presence of the uremic toxin P-cresol, the death of SH-SY5Y cells was induced by ROS-mediated ER stress. Co-culture with TUDCA-treated CKD-hMSCs increased anti-oxidant enzyme activities in SH-SY5Y cells through the upregulation of the cellular prion protein (PrPC) expression. Upregulated PrPC expression in SH-SY5Y cells protected against CKD-mediated ER stress and apoptosis. In an adenine-induced murine CKD model, injection with TUDCA-treated CKD-hMSCs suppressed ROS generation and ER stress in the hippocampus. These results indicate that TUDCA-treated CKD-hMSCs prevent the CKD-mediated cell death of SH-SY5Y cells by inhibiting ER stress. Our study suggests that treatment with TUDCA could be a powerful strategy for developing autologous MSC-based therapeutics for patients with CKD, and that PrPC might be a pivotal target for protecting neural cells from CKD-mediated ER stress.

Highlights

Chronic kidney disease (CKD) is a major global public health issue, causing several complications such as hypertension, atherosclerosis, aging, and diabetes [1]
These findings indicate that uremic toxin-mediated reactive oxygen species (ROS) induce neural cell death through activation of endoplasmic reticulum (ER) stress, and that PrPC is involved in CKD-mediated neural cell death
We provide evidence that the generation of ROS is induced in the hippocampus of an adenine-induced murine model, resulting in ROS-mediated ER stress and cell death in neural cell line SH-SY5Y cells

Summary

Introduction

Chronic kidney disease (CKD) is a major global public health issue, causing several complications such as hypertension, atherosclerosis, aging, and diabetes [1]. Kidney dysfunction leads to the excretion of uremic toxins, which accumulate in the blood and have toxic effects on several types of tissue [2]. P-cresol, one of the major uremic toxins, is a protein-bound solute that induces cell apoptosis and senescence [5]. Recent studies have revealed that P-cresol induces cellular senescence, inhibition of proliferation, and dysfunction of mitochondria in mesenchymal stem cells (MSCs) [6,7,8]. Uremic toxins such as P-cresol are a major hurdle for stem cell-based therapies, and the development of uremic toxin-resistant stem cells to treat CKD patients is urgently needed

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Results

Conclusion