In human IgA nephropathy uteroglobin does not play the role inferred from transgenic mice

Am J Kidney Dis. 2002 Sep;40(3):495-503. doi: 10.1053/ajkd.2002.34890.


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).

Conclusion: 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.

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Antibody Affinity / genetics
  • Antigen-Antibody Complex / physiology
  • Antigen-Antibody Reactions / genetics
  • Child
  • Collagenases / metabolism
  • Disease Models, Animal
  • Feedback, Physiological / genetics
  • Female
  • Fibronectins / antagonists & inhibitors
  • Fibronectins / metabolism
  • Glomerulonephritis, IGA / etiology*
  • Glomerulonephritis, IGA / genetics
  • Glomerulonephritis, IGA / pathology
  • Humans
  • Immunoglobulin A / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Proteinuria / genetics
  • Proteinuria / pathology
  • Risk Factors
  • Uteroglobin / blood
  • Uteroglobin / deficiency*
  • Uteroglobin / genetics
  • Uteroglobin / physiology*


  • Antigen-Antibody Complex
  • Fibronectins
  • Immunoglobulin A
  • Uteroglobin
  • Collagenases
  • FN type IV collagenase