Insight into the physiological function(s) of uteroglobin by gene-knockout and antisense-transgenic approaches.
To determine the physiological function(s) of uteroglobin (UG), a steroid-inducible, homodimeric, secreted protein, we have generated transgenic mice that either are completely UG-deficient due to UG gene-knockout (UG-KO) or are partially UG-deficient due to the expression of UG antisense RNA (UG-AS). Both the UG-KO and UG-AS mice develop immunoglobulin A (IgA) nephropathy (IgAN), characterized by microhematuria, albuminuria, and renal glomerular deposition of IgA, fibronectin (Fn), collagen, and C3 complement. This phenotype of both UG-KO and UG-AS mice is virtually identical to that of human IgAN, the most common primary glomerulopathy worldwide. The molecular mechanism by which UG prevents this disease in mice appears to center around UG's interaction with Fn. Since Fn, IgA, and UG are present in circulation and high plasma levels of IgA-Fn complex have been reported in human IgAN, we sought to determine whether UG interacts with Fn and prevents Fn-Fn and/or IgA-Fn interactions, essential for abnormal tissue deposition of Fn and IgA. Our coimmunoprecipitation studies uncovered the formation of Fn-UG heteromers in vitro and these heteromers are detectable in the plasma of normal mice, but not UG-KO mice. Further, high plasma levels of IgA-Fn complex, a characteristic of human IgAN patients, were also found in UG-KO mice. Finally, coadministration of UG + Fn or UG + IgA to UG-KO mice prevented glomerular deposition of Fn and IgA, respectively. Our results define a possible molecular mechanism of IgAN and provide insight into at least one important physiological function of UG in maintaining normal renal function in mice.
Zhang
Z
Z
Section on Developmental Genetics, Heritable Disorders Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1830, USA.
Kundu
G C
GC
Zheng
F
F
Yuan
C J
CJ
Lee
E
E
Westphal
H
H
Ward
J
J
DeMayo
F
F
Mukherjee
A B
AB
D000818:Animals; D003094:Collagen / Q000235:genetics; D003176:Complement C3 / Q000378:metabolism; D005353:Fibronectins / Q000097:blood / Q000235:genetics; D005920:Glomerular Mesangium / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005922:Glomerulonephritis, IGA / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D006417:Hematuria / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood; D007668:Kidney / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008822:Mice, Transgenic / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010641:Phenotype; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D016372:RNA, Antisense / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D014598:Uteroglobin / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*
D003176:Complement C3; D005353:Fibronectins; D007070:Immunoglobulin A; D010982:Platelet-Derived Growth Factor; D016372:RNA, Antisense; D012333:RNA, Messenger; D003094:Collagen; D014598:Uteroglobin