Enhanced production of glomerular extracellular matrix in a new mouse strain of high serum IgA ddY mice

Abstract

To investigate the relationship between high serum levels of IgA and glomerular lesions, selective mating was performed in high serum IgA ddY mice, a murine model of spontaneously developing mesangioproliferative glomerulonephritis mimicking human IgA nephropathy. The selection and mating of high IgA ddY mice were accomplished when the mice were three 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, although 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 semiquantitative and morphometric analyses with moderate tubulointerstitial damage. These mesangial matrices were stained markedly by antisera for collagen type IV and by fibronectin, but not by collagen type I. Localization of 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 analysis of serum IgA disclosed heterogeneous spectrotypes in a wide pH range (4.5 to 6.5), in contrast to very limited spectrotypes in the acidic 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-gp70 immune complexes with age, with no relationship to the severity of glomerular gp70 deposition. Northern blot analysis of renal tissue revealed markedly high mRNA expression of collagen type I, IV, fibronectin 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-producing B-cell clones is suggested to be closely related to the increased gene expression of TGF-beta, which induces enhanced glomerular extracellular matrix (especially fibronectin) accumulation in HIGA mice, being possibly mediated by the mesangial deposition of dimeric and highly acidic IgA. This newly established strain may provide a model for investigating the relationship between progressive glomerular sclerotic lesions and the induction of pathogenic IgA in human IgA nephropathy.

Genomic analysis of a mouse model of immunoglobulin A nephropathy reveals an enhanced PDGF–EDG5 cascade

“…2 This strain shows consistently high serum IgA levels, and various mesangial lesions are observed microscopically, from mild mesangial cell proliferation to marked mesangial expansion accompanied by extracellular matrix accumulation. 3 HIGA mice, therefore, show almost all of the clinical and pathological features of human IgAN, indicating that this is a valid animal model for human IgAN. To gain insight into the underlying molecular basis of IgAN, we have used cDNA microarrays to assess changes in gene expression in the kidneys of HIGA mice. As the genetic background of HIGA and ddY mice is considered to be similar, we used ddY mice as controls to examine the gene expression specifically related to IgAN.…”

Imaging mass spectrometry analysis reveals an altered lipid distribution pattern in the tubular areas of hyper-IgA murine kidneys

“…Hence, we investigated the distribution of lipid compositions in the kidneys of HIGA mice-well-recognized murine model for IgA nephropathy (Muso et al, 1996)-using MALDI-QIT-TOF-IMS and analyzed the physiological significance of the molecules detected by it. 7 methanol/0.1% trifluoroacetic acid) using a 0.2-mm nozzle caliber airbrush (Procon Boy FWA Platinum; Mr. Hobby, Tokyo, Japan).…”

Expression of transforming growth factor beta-1 in gastric cancer and in the gastric mucosa of first-degree relatives of patients with gastric cancer

“…This antibody is specific for TGF-β1, with no cross-reactivity with TGF-β2 or TGF-β3. Antibody specificity was confirmed by Western blotting and immunoprecipitation studies (Muso et al, 1996). Paraffin-embedded tissue sections from eight gastric cancers and six non-malignant stomachs were subjected to immunostaining using a streptavidin-peroxidase method.…”