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Uteroglobin is essential in preventing immunoglobulin A nephropathy in mice

Nature Medicine volume 5, pages 1018–1025 (1999)Cite this article

Abstract

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.

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Figure 1: Generation and characterization of the AS-UG transgenic mice.
Figure 2: Histopathological and immunohistochemical analyses of mouse kidney sections.
Figure 3: Abnormal deposition of IgA and complement C3.
Figure 4: The effects of UG on IgA–FN complex formation and IgA–FN complex binding to cultured mesangial cells.
Figure 5: Inhibition of renal glomerular deposition of exogenous IgA by UG.
Figure 6: Expression of mRNA for Fn, the α1-chain of type IV collagen and PDGF-B in the glomeruli of UG–/– mice.

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Acknowledgements

We thank I. Owens, J.Y.Chou, S.W. Levin, J.D. Butler and J.B. Sidbury Jr. for critical review of the manuscript and for suggestions. We also thank K. Takashi for discussions and support throughout this study. The photomicroscopic assistance of R. Dreyfuss and S. Everett (Medical Arts and Photography Branch, NIH) is acknowledged.

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Author notes

  1. Feng Zheng, Gopal C. Kundu and Zhongjian Zhang: F.Z., G.C.K. and Z.Z. contributed equally to this work

Authors and Affiliations

  1. Section on Developmental Genetics, Heritable Disorders Branch, The National Institute of Child Health and Human Development, The National Institutes of Health, Bethesda, 20892-1830, Maryland, USA

    Feng Zheng, Gopal C. Kundu, Zhongjian Zhang & Anil B. Mukherjee

  2. Veterinary and Tumor Pathology Section, National Cancer Institute, Frederick, 21702-1201, Maryland, USA

    Jerrold Ward

  3. Department of Cell Biology, Baylor College of Medicine, Houston, 77030, Texas, USA

    Francesco DeMayo

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  1. Feng Zheng
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Correspondence to Anil B. Mukherjee.

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Zheng, F., Kundu, G., Zhang, Z. et al. Uteroglobin is essential in preventing immunoglobulin A nephropathy in mice. Nat Med 5, 1018–1025 (1999). https://doi.org/10.1038/12458

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