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

TL;DR

This study shows that FBXO45 helps reduce cell death in kidney cells of diabetic mice by interacting with PLK1, offering a potential new treatment for diabetic nephropathy.

Contribution

The study reveals a novel interaction between FBXO45 and PLK1 in regulating ferroptosis in diabetic nephropathy.

Findings

FBXO45 mRNA levels are reduced in diabetic nephropathy patients and correlate with disease markers.

FBXO45 interacts with PLK1 at specific amino acid residues, confirmed by immunoprecipitation.

FBXO45 mitigates ferroptosis via the PLK1/GPX4/SOX2 pathway in a diabetic nephropathy model.

Abstract

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.

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.

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.

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.

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