In human IgA nephropathy uteroglobin does not play the role inferred from transgenic mice.
BACKGROUND
Uteroglobin (UG)-knockout and UG-antisense transgenic mice develop clinical and pathological features of immunoglobulin A (IgA) nephropathy with heavy proteinuria. These models suggested that UG, an anti-inflammatory protein with high affinity for fibronectin (Fn), prevents the formation of IgA-Fn complexes and mesangial deposits in mice. We aim to elucidate whether similar mechanisms underlie the development and severity of human IgA nephropathy.


METHODS
Specific enzyme-linked immunosorbent assays were devised to detect serum levels of UG binding to Fn or incorporated into IgA-Fn complexes and IgA binding to Fn or collagen IV. Sera from 75 patients with IgA nephropathy with normal renal function and various degrees of proteinuria (0.2 to 5 g/d of protein) stable over the previous 3 months without therapy were investigated and compared with healthy controls.


RESULTS
Levels of UG binding to Fn were similar in patients with IgA nephropathy and healthy controls. UG incorporated into circulating IgA-Fn complexes, as well as levels of IgA-Fn complexes and IgA binding Fn and collagen IV, were significantly greater in patients than healthy controls. Greater amounts of UG incorporated into IgA-Fn complexes reduced the risk for proteinuria with protein greater than 1 g/d (odds ratio = 0.67; P < 0.001). Logistic regression analysis assigned a predictive value for proteinuria persistently greater than 1 g/d of protein to lower amounts of UG incorporated into IgA-Fn complexes (R = -0.267; P = 0.008) and increased binding of IgA to collagen IV (R = 0.214; P = 0.0003).


CONCLUSIONS
This first report of human IgA nephropathy after the publication of the mouse model shows that UG is not reduced in circulation and is even increased in IgA-Fn complexes. Because aberrant IgA1 glycosylation is the event initiating IgA nephropathy in humans, we speculate that the enhanced incorporation of UG into IgA-Fn complexes might represent feedback to reduce the formation of macromolecular aggregates.
Coppo
Rosanna
R
Department of Nephrology, Dialysis, and Transplantation, Regina Margherita University Hospital, Turin, Italy. nefrologia@oirmsantanna.piemonte.it
Chiesa
Monica
M
Cirina
Paola
P
Peruzzi
Licia
L
Amore
Alessandro
A
D000293:Adolescent; D000328:Adult; D000818:Animals; D000915:Antibody Affinity / Q000235:genetics; D000936:Antigen-Antibody Complex / Q000502:physiology; D000937:Antigen-Antibody Reactions / Q000235:genetics; D002648:Child; D017364:Collagenases / Q000378:metabolism; D004195:Disease Models, Animal; D025461:Feedback, Physiological / Q000235:genetics; D005260:Female; D005353:Fibronectins / Q000037:antagonists & inhibitors / Q000378:metabolism; D005922:Glomerulonephritis, IGA / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D006801:Humans; D007070:Immunoglobulin A / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011507:Proteinuria / Q000235:genetics / Q000473:pathology; D012307:Risk Factors; D014598:Uteroglobin / Q000097:blood / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*
D000936:Antigen-Antibody Complex; D005353:Fibronectins; D007070:Immunoglobulin A; D014598:Uteroglobin; D017364:Collagenases; C431667:FN type IV collagenase