Bone marrow mesenchymal stem cells inhibit ferroptosis via regulating the Nrf2-keap1/p53 pathway to ameliorate chronic kidney disease injury in the rats

Abstract

Purpose

Although bone marrow mesenchymal stem cells (BMMSCs) have been reported to exhibit a protective effect on animal models of chronic kidney disease (CKD), the exact mechanisms involved require further investigation. This study aims to investigate the underlying molecular mechanisms of BMMSCs in inhibiting ferroptosis and preventing an Adriamycin (ADR)-induced CKD injury.

Methods

A rat model of long-term CKD induced through the injection of ADR administered twice weekly via the tail vein was used in this study. After BMMSCs were systemically administered through the renal artery, pathological staining, western blotting, ELISA, and transmission electron microscopy were used to analyze ferroptosis.

Results

Analyses of renal function and histopathological findings indicated that ADR-mediated renal dysfunction improved in response to the BMMSC treatment, which was also sufficient to mediate the partial reversal of renal injury and mitochondrial pathological changes. BMMSCs decreased the ferrous iron (Fe²⁺) and reactive oxygen species and elevated glutathione (GSH) and GSH peroxidase 4. Moreover, the BMMSC treatment activated the expression of ferroptosis-related regulator NF-E2-related factor 2 (Nrf2) and inhibited Keap1 and p53 in CKD rat kidney tissues.

Conclusions

BMMSCs alleviate CKD, possibly resulting from the inhibition of kidney ferroptosis by regulating the Nrf2–Keap1/p53 pathway.

Keywords:

• Chronic kidney disease
• bone marrow mesenchymal stem cells
• ferroptosis
• Nrf2-keap1/p53 signaling pathway

Acknowledgements

Not applicable.

Ethical approval

Ethical approval and consent to participate not applicable.

Consent for publication

Not applicable

Authors’ contributions

Conceptualization, L.S., F.C. and J.W.; Performed the experiments, L.S., C.S., C.X. and Y.Z.; Analyzed the data, Q.F.; Writing-original draft preparation, L.S.; Writing-review and editing, J.W. and Y.Z. modified language. All authors have read and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statements

The datasets supporting the conclusion of this article are included within the article and its Supplementary Information files.

Additional information

Funding

The current study was supported by the National Natural Science Foundation of China (grant no. 81860144), and the Yunnan Fundamental Research Projects (grant no. 202101AY070001-184).