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Valsartan- and melatonin-supported adipose-derived mesenchymal stem cells preserve renal function in chronic kidney disease rat through upregulation of prion protein participated in promoting PI3K-Akt-mTOR signaling and cell proliferation - 16/01/22

Doi : 10.1016/j.biopha.2021.112551 
Chih-Chao Yang a, Pei-Hsun Sung b, c, d, Kuan-Hung Chen c, e, Han-Tan Chai b, John Y. Chiang f, Sheung-Fat Ko g, Fan-Yen Lee h, i, Hon-Kan Yip b, c, d, j, k, l, m,
a Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan, ROC 
b Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan, ROC 
c Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan, ROC 
d Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan, ROC 
e Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan, ROC 
f Department of Computer Science and Engineering, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan, ROC 
g Department of Radiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan, ROC 
h Division of thoracic and Cardiovascular Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan, ROC 
i Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC 
j School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC 
k Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan, ROC 
l Department of Nursing, Asia University, Taichung 41354, Taiwan, ROC 
m Division of Cardiology, Department of Internal Medicine, Xiamen Chang Gung Hospital, Xiamen 361028, Fujian, China 

Corresponding author at: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan, ROC.Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung83301Taiwan, ROC

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Abstract

This study tested the hypothesis that valsartan (Val) and melatonin (Mel)-assisted adipose-derived mesenchymal stem cells (ADMSCs) preserved the residual renal function in chronic kidney disease (CKD) rat through promoting cellular-prior-protein (PrPC) to upregulate PI3K/Akt/mTOR signaling and cell proliferation. In vitro study demonstrated that as compared with CKD-derived-ADMSCs, Val/Mel/overexpression of PrPC-treated CKD derived-ADMSCs significantly upregulated cell proliferation and protein expressions of PrPC and phosphorylated (p)-PI3K/p-Akt/p-mTOR, and downregulated oxidative stress (all p < 0.001). Rats (n = 42) were categorized into group 1 (sham-operated-control), group 2 (CKD), group 3 (CKD + ADMSCs/1.2 ×106 cells) + Mel/20 mg/kg/day), group 4 (CKD + siRNA-PrPC-ADMSCs/1.2 ×106 cells), group 5 (CKD + ADMSCs/1.2 ×106 cells + Val/20 mg/kg/day) and group 6 (CKD + Val + Mel). By day 35, the kidney specimens were harvested and the result showed that the protein expression of PrPC was highest in group 1, lowest in groups 2/4 and significantly lower in group 6 than in groups 3/5, but it was similar in groups 3/5 (all p < 0.0001). The protein expressions of cell-stress-signaling (p-PI3K/p-Akt/p-mTOR) and cell-cycle activity (cyclin-D1/clyclin-E2/Cdk2/Cdk4) exhibited an identical pattern, whereas the protein expressions of oxidative-stress (NOX-1/NOX-2)/mitochondrial fission (PINK1/DRP1)/apoptosis (cleaved-capsase3/cleaved-PARP) and fibrosis (TFG-ß/Smad3) as well as creatinine/BUN levels, ratio of urine-protein to urine-creatine and kidney-injured score exhibited an opposite pattern of PrPC among the groups (all p < 0.0001). In conclusion, Mel/Val facilitated-ADMSCs preserved renal architecture and function in CKD rat through promoting PrPC to regulate the cell proliferation/oxidative-stress/cell-stress signalings.

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Graphical Abstract

The proposed underlying mechanism of Mel-Val facilitated-ADMSC protected the renal architecture and function in CKD rat through pushing forward PrPC to regulate the cell proliferation, oxidative-stress cell-stress signalings. Additionally, Mel- or Val-facilitated ADMSCs were superior to combined Mel + Val on improving the outcomes in CKD rodent.



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Highlights

Protein expression of PrPC was notably reduced in CKD-derived stem cells.
Mel and Val upregulated protein expression of PrPC in stem cells.
Val-Mel & PrPC overexpression enhanced cell-stress signaling & cell-cycle activity.
Val-Mel & PrPC overexpression preserved the renal function in CKD setting.

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Abbreviations : ADMSC, ARB, CKD, EPC, IF, IHC, KIM, Mel, MMP, PARP, PrPC, TGF, TNF, Val, ZO-1

Keywords : Cellular prior protein, Adipose-derived mesenchymal stem cells, Melatonin, Valsartan, Oxidative stress


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