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

Chih-Chao Yang; Pei-Hsun Sung; Kuan-Hung Chen; Han-Tan Chai; John Y Chiang; Sheung-Fat Ko; Fan-Yen Lee; Hon-Kan Yip

doi:10.1016/j.biopha.2021.112551

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

Biomed Pharmacother. 2022 Feb:146:112551. doi: 10.1016/j.biopha.2021.112551. Epub 2021 Dec 20.

Authors

Chih-Chao Yang¹, Pei-Hsun Sung², Kuan-Hung Chen³, Han-Tan Chai⁴, John Y Chiang⁵, Sheung-Fat Ko⁶, Fan-Yen Lee⁷, Hon-Kan Yip⁸

Affiliations

¹ Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan, ROC.
² Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan, ROC; Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan, ROC; Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan, ROC.
³ Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan, ROC; Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan, ROC.
⁴ Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan, ROC.
⁵ Department of Computer Science and Engineering, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan, ROC.
⁶ Department of Radiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan, ROC.
⁷ 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; Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC.
⁸ Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan, ROC; Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan, ROC; Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan, ROC; School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan, ROC; Department of Nursing, Asia University, Taichung 41354, Taiwan, ROC; Division of Cardiology, Department of Internal Medicine, Xiamen Chang Gung Hospital, Xiamen 361028, Fujian, China. Electronic address: han.gung@msa.hinet.net.

PMID: 34923336
DOI: 10.1016/j.biopha.2021.112551

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 (PrP^C) to upregulate PI3K/Akt/mTOR signaling and cell proliferation. In vitro study demonstrated that as compared with CKD-derived-ADMSCs, Val/Mel/overexpression of PrP^C-treated CKD derived-ADMSCs significantly upregulated cell proliferation and protein expressions of PrP^C 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-PrP^C-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 PrP^C 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 PrP^C among the groups (all p < 0.0001). In conclusion, Mel/Val facilitated-ADMSCs preserved renal architecture and function in CKD rat through promoting PrP^C to regulate the cell proliferation/oxidative-stress/cell-stress signalings.

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

MeSH terms

Animals
Cell Proliferation / drug effects
Disease Models, Animal
Dose-Response Relationship, Drug
Kidney / drug effects
Male
Melatonin / pharmacology*
Mesenchymal Stem Cells / metabolism*
Oxidative Stress / drug effects
Phosphatidylinositol 3-Kinases / drug effects
Prion Proteins / drug effects
Proto-Oncogene Proteins c-akt / drug effects
Rats
Rats, Sprague-Dawley
Renal Insufficiency, Chronic / pathology*
Signal Transduction / drug effects
TOR Serine-Threonine Kinases / drug effects
Up-Regulation
Valsartan / pharmacology*

Substances

Prion Proteins
Valsartan
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases
Melatonin