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 patholog ic features include hematuria, high levels of circulating IgA-fibronectin ( Fn) complexes, and glomerular deposition of IgA, complement C3, Fn and coll agen. We report here that two independent mouse models (gene knockout and a ntisense transgenic), both manifesting deficiency of an anti-inflammatory p rotein, 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 glom erular cells. Moreover, UG prevents glomerular accumulation of exogenous Ig A in UG-null mice. These results define an essential role for UG in prevent ing mouse IgA nephropathy and warrant further studies to determine if a sim ilar mechanism(s) underlies the human disease.