Mesenchymal stromal cells reduce ferroptosis of podocytes by activating the Nrf2/HO-1/GPX4 pathway in lupus nephritis.

Background: Ferroptosis has been reported to be involved in the occurrence and development of various kidney diseases. Emerging evidence suggests that ferroptosis also plays a critical role in systemic lupus erythematosus (SLE) and lupus nephritis (LN), contributing to podocyte injury and renal dysfunction. Mesenchymal stromal cells (MSCs) have become an attractive option for podocyte injury repairing in LN. The aim of this research was to determine whether MSCs regulate ferroptosis of podocytes in LN.

Methods: MSCs were injected into female MRL/lpr mice via tail vein. The symptoms of LN and the detection of ferroptosis-related biomarkers in podocytes were detected. In vitro validation was conducted by mouse podocyte cell line MPC-5.

Results: The occurrence of ferroptosis and involvement of Nrf2/heme oxygenase-1 (HO-1) signaling pathway in podocytes were observed. We found increased expression of the podocyte marker, Wilm's tumor 1 (WT-1) and synaptopodin, following the improvement of lupus-like symptoms after MSC transplantation in MRL/lpr mice. The expression of ferroptosis-related protein glutathione peroxidase 4 (GPX4) and long chain acyl-CoA synthetase 4 (ACSL4) were elevated in renal, along with the Nrf2 and HO-1 activity enhancement. In vitro, MSC treatment maintain a stabilization of podocyte actin stress fibers, leading to an improvement of cell viability. Furthermore, our results showed that puromycin aminonucleoside (PAN) induce accumulation of cellular lipid reactive oxygen species (ROS) and glutathione depletion, and the expression of Nrf2, HO-1 and GPX4 were all downregulated whereas the expression of ACSL4 was upregulated. However, these effects were reversed by MSCs and ferroptosis inhibitor ferrastatin-1 (Fer-1). The promotion of Nrf2 nuclear translocation was observed after the treatment with MSCs.

Conclusion: Ferroptosis activation is involved in the development of LN. MSCs could ameliorate podocyte injury in LN by inhibiting ferroptosis through the Nrf2/HO-1/GPX4 pathway, which will provide novel potential therapeutic targets for LN.