FBXO45 levels regulated ferroptosis renal tubular epithelial cells in a model of diabetic nephropathy by PLK1.

ABSTRACT

Objective: This research aims to investigate the role and underlying biological mechanism of FBXO45 in regulating ferroptosis of renal fibrocytes in a diabetic nephropathy (DN) model. Methods: C57BL/6 mice were fed with a high-fat diet and injected with streptozotocin to induce diabetes. Human renal glomerular endothelial cells stimulated with d-glucose. Results: Serum FBXO45 mRNA expression was found to be down-regulated in patients with DN. There was a negative correlation between the expression of serum FBXO45 mRNA and serum α-SMA, Collagen I, and E-cadherin mRNA in patients with DN. Additionally, the expression of serum FBXO45 mRNA showed a negative correlation with blood sugar levels. Based on a 3D model prediction, it was observed that FBXO45 interacts with polo-like kinase 1 (PLK1) at GLY-271, ILE-226, GLY-166, LEU-165, ARG-245, and ASN-220, while PLK1 interacts with FBXO45 at TYR-417, ARG-516, HIS-489, TYR-485, GLN-536, and ARG-557. This interaction was confirmed through immunoprecipitation assay, which showed the interlinking of FBXO45 protein with PLK1 protein. Conclusions: These findings indicate that FBXO45 plays a role in mitigating ferroptosis in DN through the regulation of the PLK1/GPX4/SOX2 pathway. This highlights the potential of targeting FBXO45 as a therapeutic approach to ameliorate ferroptosis in DN.