The pathogenic roles of glomerular deposition of components of the
complement cascade in
IgA nephropathy (IgAN) are not completely clarified. To investigate the pathologic role of
complement pathways in IgAN, two IgAN-prone mouse models were examined. Grouped ddY (gddY) mice showed significant high
proteinuria, severe glomerular lesions, and extracellular matrix expansion compared with high serum
IgA (HIGA) mice but with similar intensity of glomerular
IgA deposition. Glomerular activation of the classical,
lectin, and alternative pathways was demonstrated by significantly stronger staining for
complement (C)3,
C5b-9, C1q, C4,
mannose-binding lectin (MBL)-A/C, MBL-associated
serine protease-2, and
factor B and
properdin in gddY mice than in HIGA mice. Similarly, the serum levels of
IgA-
IgG2a/
IgM and
IgA-MBL-A/C
immune complexes and
polymeric IgA were significantly higher in gddY mice than in HIGA mice. Moreover, the serum levels of aberrantly
glycosylated IgA characterized by the binding of Sambucus nigra bark
lectin and
Ricinus communis agglutinin I were significantly higher in gddY mice than in HIGA mice. This aberrancy in glycosylation was confirmed by
monosaccharide compositional analysis of purified
IgA using gas-liquid chromatography. This study is the first to demonstrate that aberrantly
glycosylated IgA may influence the formation of macromolecular
IgA including
IgA-
IgG immune complexes and subsequent complement activation, leading to full progression of IgAN.