Uteroglobin is essential in preventing immunoglobulin A nephropathy in mice.
The molecular mechanism(s) of immunoglobulin A (IgA) nephropathy, the most common primary renal glomerular disease worldwide, is unknown. Its pathologic features include hematuria, high levels of circulating IgA-fibronectin (Fn) complexes, and glomerular deposition of IgA, complement C3, Fn and collagen. We report here that two independent mouse models (gene knockout and antisense transgenic), both manifesting deficiency of an anti-inflammatory protein, uteroglobin (UG), develop almost all of the pathologic features of human IgA nephropathy. We further demonstrate that Fn-UG heteromerization, reported to prevent abnormal glomerular deposition of Fn and collagen, also abrogates both the formation of IgA-Fn complexes and their binding to glomerular cells. Moreover, UG prevents glomerular accumulation of exogenous IgA in UG-null mice. These results define an essential role for UG in preventing mouse IgA nephropathy and warrant further studies to determine if a similar mechanism(s) underlies the human disease.
Zheng
F
F
Section on Developmental Genetics, Heritable Disorders Branch, The National Institute of Child Health and Human Development, The National Institutes of Health, Bethesda, Maryland 20892-1830, USA.
Kundu
G C
GC
Zhang
Z
Z
Ward
J
J
DeMayo
F
F
Mukherjee
A B
AB
D000818:Animals; D000936:Antigen-Antibody Complex / Q000032:analysis / Q000097:blood / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D003176:Complement C3 / Q000032:analysis / Q000276:immunology; D004195:Disease Models, Animal; D005353:Fibronectins / Q000032:analysis / Q000097:blood / Q000235:genetics / Q000276:immunology; D017353:Gene Deletion; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D005922:Glomerulonephritis, IGA / Q000235:genetics / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology; D006417:Hematuria / Q000473:pathology / Q000652:urine; D006801:Humans; D007070:Immunoglobulin A / Q000032:analysis / Q000097:blood / Q000187:drug effects / Q000276:immunology*; D007678:Kidney Glomerulus / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010982:Platelet-Derived Growth Factor / Q000032:analysis / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics; D020574:Proto-Oncogene Proteins c-sis; D016372:RNA, Antisense / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014598:Uteroglobin / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*
D000936:Antigen-Antibody Complex; D003176:Complement C3; D005353:Fibronectins; D007070:Immunoglobulin A; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; D020574:Proto-Oncogene Proteins c-sis; D016372:RNA, Antisense; D012333:RNA, Messenger; D003094:Collagen; D014598:Uteroglobin