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(American Journal of Pathology. 2007;170:447-456.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060559

Development of Immunoglobulin A Nephropathy- Like Disease in ß-1,4-Galactosyltransferase-I-Deficient Mice

Toshikazu Nishie*, Osamu Miyaishi{dagger}, Haruhito Azuma{ddagger}, Akihiko Kameyama§, Chie Naruse*, Noriyoshi Hashimoto*, Hitoshi Yokoyama, Hisashi Narimatsu§, Takashi Wada and Masahide Asano*

From the Division of Transgenic Animal Science,* Advanced Science Research Center, Kanazawa University, Kanazawa; the Department of Pathology,{dagger} Aichi Medical University School of Medicine, Aichi; the Department of Urology,{ddagger} Osaka Medical College, Osaka; the Glycogene Function Team,§ Research Center for Glycoscience, National Institute of Advanced Industrial Science and Technology, Ibaraki; and the Department of Disease Control and Homeostasis, Graduate School of Medical Science and Division of Blood Purification, Kanazawa University, Kanazawa, Japan

ß4 Galactosylation of glycoproteins plays important roles in protein conformation, stability, transport, and clearance from the circulation. Recent studies have revealed that aberrant glycosylation causes various human diseases. Here we report that mice lacking ß-1,4-galactosyltransferase (ß4GalT)-I, which transfers galactose to the terminal N-acetylglucosamine of N- and O-linked glycans in a ß-1,4 linkage, spontaneously developed human immunoglobulin A nephropathy (IgAN)-like glomerular lesions with IgA deposition and expanded mesangial matrix. ß4GalT-I-deficient mice also showed high serum IgA levels with increased polymeric forms as in human IgAN. IgAN is the most common form of glomerulonephritis, and a significant proportion of patients progress to renal failure. However, pathological molecular mechanisms of IgAN are poorly understood. In humans, abnormal character of serum IgA, especially serum IgA1 with aberrant galactosylation and sialylation of O-glycans in its hinge region is thought to contribute to the pathogenesis of IgAN. Mouse IgA has N-glycans but not O-glycans, and ß4-galactosylation and sialylation of the N-glycans on the serum IgA from ß4GalT-I-deficient mice was completely absent. This is the first report demonstrating that genetic remodeling of protein glycosylation causes IgAN. We propose that carbohydrates of serum IgA are involved in the development of IgAN, whether the carbohydrates are O-glycans or N-glycans.




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