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

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

^*Corresponding author for this work

School of Traditional Chinese Medicine

Research output: Contribution to journal › Journal Article › peer-review

19 Scopus citations

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.

Original language	English
Article number	112551
Journal	Biomedicine and Pharmacotherapy
Volume	146
DOIs	https://doi.org/10.1016/j.biopha.2021.112551
State	Published - 02 2022

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Publisher Copyright:
© 2021 The Authors

Keywords

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

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Yang, C. C., Sung, P. H., Chen, K. H., Chai, H. T., Chiang, J. Y., Ko, S. F., Lee, F. Y., & Yip, H. K. (2022). 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. Biomedicine and Pharmacotherapy, 146, Article 112551. https://doi.org/10.1016/j.biopha.2021.112551

@article{3d343083dbe94ad7b254127b715b4b3c,

title = "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",

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.",

keywords = "Adipose-derived mesenchymal stem cells, Cellular prior protein, Melatonin, Oxidative stress, Valsartan",

author = "Yang, {Chih Chao} and Sung, {Pei Hsun} and Chen, {Kuan Hung} and Chai, {Han Tan} and Chiang, {John Y.} and Ko, {Sheung Fat} and Lee, {Fan Yen} and Yip, {Hon Kan}",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2022",

month = feb,

doi = "10.1016/j.biopha.2021.112551",

language = "英语",

volume = "146",

journal = "Biomedicine and Pharmacotherapy",

issn = "0753-3322",

publisher = "Elsevier Masson s.r.l.",

}

Yang, CC, Sung, PH, Chen, KH, Chai, HT, Chiang, JY, Ko, SF, Lee, FY & Yip, HK 2022, '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', Biomedicine and Pharmacotherapy, vol. 146, 112551. https://doi.org/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. / Yang, Chih Chao; Sung, Pei Hsun; Chen, Kuan Hung et al.
In: Biomedicine and Pharmacotherapy, Vol. 146, 112551, 02.2022.

Research output: Contribution to journal › Journal Article › peer-review

TY - JOUR

T1 - 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

AU - Yang, Chih Chao

AU - Sung, Pei Hsun

AU - Chen, Kuan Hung

AU - Chai, Han Tan

AU - Chiang, John Y.

AU - Ko, Sheung Fat

AU - Lee, Fan Yen

AU - Yip, Hon Kan

PY - 2022/2

Y1 - 2022/2

N2 - 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.

AB - 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.

KW - Adipose-derived mesenchymal stem cells

KW - Cellular prior protein

KW - Melatonin

KW - Oxidative stress

KW - Valsartan

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U2 - 10.1016/j.biopha.2021.112551

DO - 10.1016/j.biopha.2021.112551

M3 - 文章

C2 - 34923336

AN - SCOPUS:85123812797

SN - 0753-3322

VL - 146

JO - Biomedicine and Pharmacotherapy

JF - Biomedicine and Pharmacotherapy

M1 - 112551

ER -

Yang CC, Sung PH, Chen KH, Chai HT, Chiang JY, Ko SF et al. 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. Biomedicine and Pharmacotherapy. 2022 Feb;146:112551. 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

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