Abstract
INTRODUCTION: C3 glomerulopathy (C3G) is caused by dysregulation of complement activation. Our previous study found that patients with C3G showed rare variants in von Willebrand factor (vWF). However, the role of vWF in the pathogenesis of C3G is still unclear. METHOD: Patients with C3G diagnosed using kidney biopsy in Peking University First Hospital from 2012 to 2021 were included in the study. The levels of vWF in plasma, urine, and kidney specimens of patients with C3G were detected using enzyme-linked immunosorbent assay (ELISA) or immunofluorescence, respectively, and their associations with clinicopathological data were analyzed. VWF-knockout C3G (FH (m/m) P (-/-) VWF (m/m) ) mice were generated using the CRISPR/Cas9 system to examine the cellular and molecular mechanisms. RESULTS: There were 44 patients with C3G included. The urinary level of vWF-to-creatinine ratio (vWF/Cr) in patients with C3G was associated with the level of serum creatinine (Scr) (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 (hazard ratio: 1.294, 95% CI: 1.050-1.595, P = 0.015). vWF was colocalized with C3 and C5b-9 in kidneys. Compared with FH (m/m) P (-/-) mice, FH (m/m) P (-/-) VWF (m/m) mice showed significantly higher levels of Scr (140.70 ± 61.87 vs. 31.39 ± 12.28 μmol/l, P < 0.001), protein creatinine ratio (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/m) P (-/-) VWF (m/m) mice. CONCLUSION: The levels of vWF were associated with disease severity and poor prognosis of patients with C3G. 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.