Kidney Week

Abstract: FR-PO808

The Role of von Willebrand Factor (vWF) in the Pathogenesis of C3 Glomerulopathy (C3G)

Session Information

• Glomerular Diseases: Inflammation and Immunology
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Author

• Hua, Zixin, Peking University First Hospital, Beijing, Beijing, China

Zixin Hua, DrPH

Background

C3G is caused by dysregulation of complement activation. Our previous study found that C3G patients showed rare variants in vWF. However, role of vWF in C3G's pathogenesis remains unclear.

Methods

The levels of vWF in plasma, urine and kidney specimens of C3G patients were detected and their associations with clinicopathological data were analyzed. A VWF-knockout C3G (FH^m/mP^-/-VWF^m/m) mice was generated using the CRISPR/Cas9 system to examine the cellular and molecular mechanisms.

Results

The urinary level of vWF/Cr in C3G patients was associated with level of serum creatinine (r=0.627, P<0.001), proteinuria (r=0.505, P=0.010), serum C3 (r=-0.582, P=0.004), and was a risk factor for worse prognosis (HR 1.294, 95% CI 1.050-1.595, P=0.015). VWF was co-localized with C3 and C5b-9 in kidneys. Compared with FH^m/mP^-/- mice, FH^m/mP^-/-VWF^m/m mice showed significantly higher levels of serum creatinine (140.70±61.87 vs 31.39±12.28 μmol/L, P<0.001), proteinuria (3.50±2.25 vs 0.86±0.11 g/mol, P<0.001), more severe renal pathological manifestations, more renal C3 and C5b-9 deposition, and worse prognosis (P=0.001). VWF gene deficiency was associated with complement factor H (FH) overexpression in FH^m/mP^-/-VWF^m/m mice.

Conclusion

The levels of vWF were associated with disease severity and poor prognosis of C3G patients. VWF gene deficiency led to the aggravation of kidney damage and FH overexpression in C3G mouse model, which indicated that vWF might play a protective role in the pathogenesis of C3G.

Associations of vWF levels with histopathological data in C3G patients

Mechanism of aberrant complement activation in VWF knockout C3G mice

Funding

• Government Support – Non-U.S.