Development of a model of early-onset IgA nephropathy.
ddY mice spontaneously develop IgA nephropathy (IgAN) with a variable age of disease onset. Establishing a model with early-onset IgAN could aid the investigation of mechanisms that underlie the pathogenesis of this disease. On the basis of histologic grading in serial biopsies, we previously classified ddY mice into early-onset, late-onset, and quiescent groups. Here, we selectively mated mice with the early-onset phenotype for >20 generations and established "grouped ddY" mice that develop IgAN within 8 weeks of age. Similar to human IgAN, the prognosis was worse for male mice than females. These mice homogeneously retained genotypes of four marker loci previously associated with the early-onset phenotype, confirming a close association of these loci with early-onset IgAN in ddY mice. Grouped ddY mice comprised two sublines, however, which had distinct genotypes at a susceptibility locus for high serum IgA levels, which maps within the Ig heavy-chain gene complex. The subline bearing the Igh-2(a) IgA allotype had a more rapid course of fatal disease and lower oligosaccharide content, suggesting that aberrant IgA glycosylation may promote the progression of murine IgAN. Taken together, these data indicate that grouped ddY mice may be a useful model for the identification of susceptibility genes and the underlying molecular mechanisms involved in the pathogenesis of human IgAN.
Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Keiko
K
Okazaki
Yusuke
Y
Suzuki
Mareki
M
Otsuji
Hitoshi
H
Suzuki
Masao
M
Kihara
Tadahiro
T
Kajiyama
Azusa
A
Hashimoto
Hiroyuki
H
Nishimura
Rhubell
R
Brown
Stacy
S
Hall
Jan
J
Novak
Shozo
S
Izui
Sachiko
S
Hirose
Yasuhiko
Y
Tomino
D017668:Age of Onset; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005922:Glomerulonephritis, IGA / Q000235:genetics; D006031:Glycosylation; D007126:Immunoglobulin Allotypes; D008297:Male; D051379:Mice; D011507:Proteinuria; D051437:Renal Insufficiency; D012737:Sex Factors
D007126:Immunoglobulin Allotypes