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
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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.
Le texte complet de cet article est disponible en PDF.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.
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. |
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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