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Molecular studies of lupus nephritis kidneys

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Abstract

Lupus nephritis is a devastating complication of systemic lupus erythematosus (SLE) for which current therapies are insufficiently effective. Histologic evaluation of renal biopsies is a poor predictor of therapeutic response or outcome. Integrated immunologic, genomic and proteomic approaches may yield new insights into disease pathogenesis and thereby improve therapeutic strategies for lupus nephritis. Given the lack of sequential biopsies from humans, it also remains essential to study informative animal models of disease. Cross-species analyses can identify cells or pathways that are relevant to human disease and can be further studied in mouse models. Using a systems biology approach in which we compare molecular data from kidneys of three different mouse models of lupus nephritis with data from human lupus biopsies, we have found that inflammatory events escalate rapidly around the time of proteinuria onset. This is followed by hypoxia and metabolic stress, and by tubular and endothelial dysfunction. The failure of complete reversal of these abnormalities may increase the sensitivity of the kidney to further insult. We further found that renal macrophages and dendritic cells are key players in lupus nephritis both in mouse models and humans and that macrophages display a hybrid molecular profile that reflects incomplete resolution of inflammation and excessive tissue remodeling. Finally, our studies have suggested several new biomarkers for disease stage that can now be tested longitudinally in human SLE patients.

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Acknowledgments

These studies were funded by grants from the Lupus Research Institute, the Alliance for Lupus Research, the Kirkland Foundation and the National Institutes of Health.

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Authors and Affiliations

  1. Center for Autoimmunity and Musculoskeletal Diseases, Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, New York, NY, 11030, USA

    Anne Davidson, Ramalingam Bethunaickan & Ranjit Sahu

  2. Department of Medicine, Mount Sinai Medical Center, New York, NY, 10029, USA

    Weijia Zhang

  3. Department of Internal Medicine, Nephrology, University of Michigan, Ann Arbor, MI, 48109, USA

    Celine Berthier & Matthias Kretzler

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  1. Anne Davidson
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  2. Ramalingam Bethunaickan
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  3. Celine Berthier
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  6. Matthias Kretzler
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Correspondence to Anne Davidson.

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Davidson, A., Bethunaickan, R., Berthier, C. et al. Molecular studies of lupus nephritis kidneys. Immunol Res 63, 187–196 (2015). https://doi.org/10.1007/s12026-015-8693-6

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