ENHANCED PRODUCTION OF GLOMERULAR EXTRACELLULAR-MATRIX IN A NEW MOUSESTRAIN OF HIGH SERUM IGA DDY MICE

To investigate the relationship between high serum levels of IgA and g lomerular lesions, selective mating was performed in high serum IgA dd Y mice, a murine model of spontaneously developing mesangioproliferati ve glomerulonephritis mimicking human IgA nephropathy. The selection a nd mating of high IgA ddY mice were accomplished when the mice were th ree to four months old. In the 12th generation of high IgA ddY (HIGA) mice, significantly higher levels of serum IgA from 10 age weeks to 60 weeks (P < 0.0002 to 0.0001) were observed in comparison with BALB/c mice. Relatively high proteinuria was observed at 40 weeks of age, alt hough hematuria was consistently negative. Microscopic observations of renal tissue disclosed a marked glomerular mesangial matrix increase and a reduction of cell proliferation with age by both semiquantitativ e and morphometric analyses with moderate tubolointersitial damage. Th ese mesangial matrices were stained markedly by antisera for collagen type IV and by fibronectin, but not by collagen type I. Localization o f TGF-beta protein was also detected in the mesangium of the HIGA mice . The positive mesangial IgA deposition was maintained consistently by this mating procedure and became more marked with age. Size analysis of IgA from ten pooled HIGA mice aged 50 to 60 weeks revealed dominant polymeric IgA in sera and dimeric IgA in glomerular eluates. Clonal a nalysis of serum IgA disclosed heterogeneous spectrotypes in a wide pH range (4.5 to 6.5) in contrast to very limited spectrotypes in the ac idic pH range (4.5 to 5.2) of IgA in the glomerular eluates from these mice. The analyses of retroviral gp70 antigen involvement in the HIGA mice disclosed a significant increase of serum levels of gp70 anti-gp 70 immune complexes with age, with no relationship to the severity of glomerular gp70 deposition. Northern blot analysis of renal tissue rev ealed markedly high mRNA expression of collagen type I, IV, fibronecti n and TGF-beta even in 10-week-old HIGA mice in comparison with BALB/c mice. The expression became more significant in 60-week-old animals. The genetic background required to induce the expansion of IgA-produci ng B-cell clones is suggested to be closely related to the increased g ene expression of TGF-beta, which induces enhanced glomerular extracel lular matrix (especially fibronectin) accumulation in HIGA mice, being possibly mediated by the mesangial deposition of dimeric and highly a cidic IgA. This newly established strain may provide a model for inves tigating the relationship between progressive glomerular sclerotic les ions and the induction of pathogenic IgA in human IgA nephropathy.