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

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 (FHm/mP-/-VWFm/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 FHm/mP-/- mice, FHm/mP-/-VWFm/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 FHm/mP-/-VWFm/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. Funding: Government Support – Non-U.S.Associations of vWF levels with histopathological data in C3G patientsMechanism of aberrant complement activation in VWF knockout C3G mice