Rapamycin Improves Adipose-Derived Mesenchymal Stem Cells (ADMSCs) Renoprotective Effect against Cisplatin-Induced Acute Nephrotoxicity in Rats by Inhibiting the mTOR/AKT Signaling Pathway

Amira Awadalla; Abdelaziz M Hussein; Yousra M El-Far; Fardous F El-Senduny; Nashwa Barakat; Eman T Hamam; Hanaa M Abdeen; Mohamed El-Sherbiny; Mohamed S Serria; Amira A Sarhan; Asmaa M Sena; Ahmed A Shokeir

doi:10.3390/biomedicines10061295

Rapamycin Improves Adipose-Derived Mesenchymal Stem Cells (ADMSCs) Renoprotective Effect against Cisplatin-Induced Acute Nephrotoxicity in Rats by Inhibiting the mTOR/AKT Signaling Pathway

Biomedicines. 2022 May 31;10(6):1295. doi: 10.3390/biomedicines10061295.

Authors

Affiliations

¹ Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt.
² Medical Physiology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt.
³ Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
⁴ Biochemistry Division, Chemistry Department, Faculty of Sciences, Mansoura University, Mansoura 35516, Egypt.
⁵ Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt.
⁶ Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, Riyadh 13713, Saudi Arabia.
⁷ Department of Anatomy, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt.

Abstract

Objective: Because the poor survival of transplanted cells in a hostile microenvironment limits stem cell therapy, in the current study, we investigated the effect of rapamycin (Rapa)-preactivated autophagy on the survival and homing of transplanted adipose mesenchymal stem cells (ADMSCs) in a rat model of cisplatin (Cis)-induced nephrotoxicity, as well as the possible role of the mTOR/AKT signaling pathway.

Materials and methods: In vitro, ADMSCs isolated from rats were treated with 50 nmol/L rapamycin for 2 h, after which the cytoprotective and autophagy-inducing effects of Rapa were investigated. The cis-induced acute nephrotoxicity rat model was constructed in vivo. ADMSCs and Rapa-ADMSCs were administered into the tail vein before Cis therapy. At 3, 7, and 10 days after Cis injection, all animals were euthanized. The renal functions and morphology as well as autophagy response were assessed.

Results: The pretreatment of cultured ADMSCs with Rapa caused a significant increase in autophagic activities and lysosome production of the cells, with a significant increase in the secretion of SDF-1, IL-10 and autophagy promoter LC3 and Beclin from these cells, while mTOR/AKT pathways were inhibited. In addition, the transplantation of Rapa-pretreated ADMSCs restored the kidney functions and morphology dramatically. Renal expression of SDF-1 and HIF1 was upregulated, while expression of IL-6, NF-kB and TGF-β1 was downregulated.

Conclusions: We concluded that the preactivation of autophagy with Rapa improves the survival and differentiation of the transplanted ADMSCs by inhibiting the mTOR/AKT signaling pathway, which in turn could significantly attenuate the Cis-induced acute renal injury.

Keywords: adipose-derived stem cells; autophagy; cisplatin-nephrotoxicity; rapamycin.

Grants and funding

This work was funded by Ministry of Higher Education, Egypt (grant # CEP1-031-MANS). Ahmed A. Shokeir was supported by the Urology and Nephrology Center, Mansoura University, Egypt.