Kidney Week

Abstract: FR-PO1050

Cellular Prion Protein Attenuates Renal Fibrosis by Interaction with Epithelial Growth Factor Receptor

Session Information

• CKD Mechanisms: Progression, Fibrosis, and Beyond
  November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2303 CKD (Non-Dialysis): Mechanisms

Author

• Song, Nana, Zhongshan Hospital Fudan University Department of Nephrology, Shanghai, China

Nana Song,

Background

Cellular prion protein (Prp^c) coded by the Prnp gene, is a kind of cell-surface copper-binding protein, anchoring on cell membrane lipid rafts through glycosyl phosphatidyl inositol anchor (GPI), and plays an important role in cell information transmission. Prp^c is expressed in the kidney. However, the role of Prp^c in regulating fibrotic maladaptive repair of the injured kidney remains largely unknown.

Methods

Wild-type FVB mice, Prnp^-/- mice were used for in vivo studies. Renal I/R injury model was induced by bilateral renal pedicle clamping for 35 minutes. Renal fibrosis models were induced by unilateral renal pedicle clamping for 30 minutes (UIR) and by unilateral ureteral obstruction (UUO). HK-2 cells were used for in vitro studies. HK-2 cells were treated with TGF-β induce EMT.

Results

Prp^c is overexpressed in the kidney biopsies from patients with CKD. This is supported by our experimental data showing that Prp^c is gradually upregulated in the kidney following I/R, UIR and UUO insult and Prp^c deletion by knocking out Prnp promoted AKI and facilitated fibrosis at later stages. Proteomics analysis indicated that the expression of key protein in DDR, including replication protein A (RPA), minichromosome maintenance protein 2/4/6 (MCM2/4/6) and cyclin-dependent kinases 1/2 (CDK1/2), as well as epidermal growth factor receptor (EGFR) drastically upregulate in the I/R kidney, while in Prnp^-/- mice, EGFR rises even further with DDR-associated protein slumping. Furthermore, we uncover a critical role of Prp^c in the control of EGFR signaling by promoting internalization of EGFR in renal tubular epithelia cells, which in turn influences DNA replication followed injury and renal fibrosis.

Conclusion

In summary, our study provides experimental evidence showing that Prp^c plays an adaptive nephroprotective role by modulating activation of EGFR pathway and promoting cell cycle progression.

Funding

• Government Support – Non-U.S.