RT Journal Article
T1 Elevated factor H-related protein 1 and factor H pathogenic variants decrease complement regulation in IgA nephropathy.
A1 Tortajada, Agustín
A1 Gutiérrez, Eduardo
A1 Goicoechea de Jorge, Elena
A1 Anter, Jaouad
A1 Segarra, Alfons
A1 Espinosa, Mario
A1 Blasco, Miquel
A1 Roman, Elena
A1 Marco, Helena
A1 Quintana, Luis F
A1 Gutiérrez, Josué
A1 Pinto, Sheila
A1 Lopez-Trascasa, Margarita
A1 Praga, Manuel
A1 Rodriguez de Córdoba, Santiago
K1 CFH mutation
K1 IgAN
K1 complement alternative pathway
K1 factor H
K1 factor H-related proteins
AB IgA nephropathy (IgAN), a frequent cause of chronic kidney disease worldwide, is characterized by mesangial deposition of galactose-deficient IgA1-containing immune complexes. Complement involvement in IgAN pathogenesis is suggested by the glomerular deposition of complement components and the strong protection from IgAN development conferred by the deletion of the CFHR3 and CFHR1 genes (ΔCFHR3-CFHR1). Here we searched for correlations between clinical progression and levels of factor H (FH) and FH-related protein 1 (FHR-1) using well-characterized patient cohorts consisting of 112 patients with IgAN, 46 with non-complement-related autosomal dominant polycystic kidney disease (ADPKD), and 76 control individuals. Patients with either IgAN or ADPKD presented normal FH but abnormally elevated FHR-1 levels and FHR-1/FH ratios compared to control individuals. Highest FHR-1 levels and FHR-1/FH ratios are found in patients with IgAN with disease progression and in patients with ADPKD who have reached chronic kidney disease, suggesting that renal function impairment elevates the FHR-1/FH ratio, which may increase FHR-1/FH competition for activated C3 fragments. Interestingly, ΔCFHR3-CFHR1 homozygotes are protected from IgAN, but not from ADPKD, and we found five IgAN patients with low FH carrying CFH or CFI pathogenic variants. These data support a decreased FH activity in IgAN due to increased FHR-1/FH competition or pathogenic CFH variants. They also suggest that alternative pathway complement activation in patients with IgAN, initially triggered by galactose-deficient IgA1-containing immune complexes, may exacerbate in a vicious circle as renal function deterioration increase FHR-1 levels. Thus, a role of FHR-1 in IgAN pathogenesis is to compete with complement regulation by FH.
YR 2017
FD 2017-06-19
LK http://hdl.handle.net/10668/11330
UL http://hdl.handle.net/10668/11330
LA en
DS RISalud
RD Apr 9, 2025