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.