Tauroursodeoxycholic Acid Protects against the Effects of P-Cresol-Induced Reactive Oxygen Species via the Expression of Cellular Prion Protein

Abstract

Mesenchymal stem cells (MSCs) could be a promising solution in the treatment of various diseases including chronic kidney disease (CKD). However, endoplasmic reticulum (ER) stress induced by ischemia in the area of application limits the integration and survival of MSCs in patients. In our study, we generated ER stress-induced conditions in MSCs using P-cresol. As P-cresol is a toxic compound accumulated in the body of CKD patients and induces apoptosis and inflammation through reactive oxygen species (ROS), we observed ER stress-induced MSC apoptosis activated by oxidative stress, which in turn resulted from ROS generation. To overcome stress-induced apoptosis, we investigated the protective effects of tauroursodeoxycholic acid (TUDCA), a bile acid, on ER stress in MSCs. In ER stress, TUDCA treatment of MSCs reduced ER stress-associated protein activation, including GRP78, PERK, eIF2α, ATF4, IRE1α, and CHOP. Next, to explore the protective mechanism adopted by TUDCA, TUDCA-mediated cellular prion protein (PrPC) activation was assessed. We confirmed that PrPC expression significantly increased ROS, which was eliminated by superoxide dismutase and catalase in MSCs. These findings suggest that TUDCA protects from inflammation and apoptosis in ER stress via PrPC expression. Our study demonstrates that TUDCA protects MSCs against inflammation and apoptosis in ER stress by PrPC expression in response to P-cresol exposure.

Melatonin protects chronic kidney disease mesenchymal stem cells against senescence via PrPC‐dependent enhancement of the mitochondrial function

“…However, one of the major drawbacks of MSC therapy is the exposure of MSCs harvested from CKD patients to endogenous uremic toxins that decrease their proliferative capacity and accelerate senescence, thereby decreasing the therapeutic potential . Cells within these patients reportedly exhibit dysfunctional mitochondrial‐related intracellular machinery and disrupted mitochondrial homeostasis, rendering CKD‐derived MSCs more prone to pathological damage .…”

Pioglitazone Protects Mesenchymal Stem Cells against P-Cresol-Induced Mitochondrial Dysfunction via Up-Regulation of PINK-1

“…Previous studies have revealed that PC suppresses the functionality of human bone marrow MSCs [ 8 ]. Our previous studies also indicated that PC led to apoptosis and senescence in MSCs [ 9 , 10 ]. This study revealed that PC induced MSC apoptosis through regulation of pro- and anti-apoptosis-associated proteins, whereas treatment with pioglitazone blocked PC-induced apoptosis.…”

“…Recent studies have shown that PC reduces the functionalities of MSCs [ 8 , 9 ]. PC induces cell apoptosis by PC-mediated oxidative stress [ 10 ]. Furthermore, PC suppresses mitochondrial respiration, leading to cellular damage in CKD patients [ 11 , 12 ].…”

Tauroursodeoxycholate—Bile Acid with Chaperoning Activity: Molecular and Cellular Effects and Therapeutic Perspectives

“…Treatment with TUDCA alleviated ER stress and decreased inflammation. Interestingly, these cytoprotective effects of TUDCA were abolished when prion protein (PrPc) was knocked down, suggesting a PrPc-dependent mode of action [165]. Altogether, these results suggested that the anti-apoptotic and anti-inflammatory effects of TUDCA are indeed preceded by mitigation of ER stress.…”

“…Indeed, such dependencies have been demonstrated in several reports concerning different types of inflammation-related disease models. It has been demonstrated that in mesenchymal stem cells (MSCs), P-cresol-induced ER stress resulted in apoptotic and inflammatory responses [165]. Upon P-cresol exposure, pro-inflammatory mediators such as p-NF-κB, p-JNK, and p-p38 were significantly overexpressed.…”