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AB0013 Glomerular IL-4 Signaling Mediates Foot Process Effacement and Proteinuria in Nephrotic Syndromes
  1. A.H. Kim1,
  2. S. Akilesh2,
  3. A. Koziell3,
  4. B. Saunders4,
  5. S. Jain5,
  6. J. Hodgin6,
  7. B. Zinselmeyer4,
  8. T. Stappenback4,
  9. J. Miner5,
  10. A. Shaw7
  1. 1Rheumatology, Washington University School of Medicine, Saint Louis, MO
  2. 2Pathology, University of Washington, Seattle, WA, United States
  3. 3Experimental Immunobiology, King's College, London, United Kingdom
  4. 4Pathology and Immunology
  5. 5Renal, Washington University School of Medicine, Saint Louis, MO
  6. 6Pathology, University of Michigan, Ann Arbor, MI
  7. 7Genentech, Inc., South San Francisco, CA, United States

Abstract

Background Podocyte foot process effacement is a feature of proteinuria, thought to be a stereotyped response of the podocyte to injury. The stimulus for podocyte injury and foot process effacement is unknown, although changes in the actin cytoskeleton has been implicated. B cell depletion therapies have demonstrated efficacy in some patients with proteinuria including those with minimal change disease. Since pathogenic antibodies are not causative, we hypothesized that a B cell derived cytokine might be capable of directly inducing podocyte injury and foot process effacement.

Objectives Develop a B cell model of proteinuria in mice, and identify glomerulopathic cytokines derived from B cells.

Methods B cell model antigen model hen egg lysozyme (HEL) was biotinylated, complexed to avidin and injected into mice. HEL-specific B cells were adoptively transferred and proteinuria assessed. Two-photon microscopy was performed in vibrotomed kidneys following transfer of CFSE-labeled HEL-specific B cells with or without HEL antigen injection. Cultured podocyte membrane ruffling was assessed with DIC videomicroscopy. IL-4 expression in mice was achieved by hydrodynamically injecting murine IL-4 in the piggyBac vector system. Human kidney biopsies were assessed for phospho-STAT6 by immunohistochemistry.

Results We identified IL-4 as a B cell derived cytokine capable of stimulating podocyte actin rearrangement. Using a novel model of B cell induced proteinuria, B cells polarized to secrete IL-4 upon activation with HEL induced proteinuria without antibody or complement deposition. Using two-photon microscopy, we observed an accumulation of HEL-specific B cells within glomeruli containing HEL antigen.

To confirm the glomerulopathic properties of IL-4, we overexpressed IL-4 in mice and found this was sufficient to induce foot process effacement and proteinuria. Inhibition of IL-4 signaling with a JAK1/3 inhibitor markedly reduced proteinuria in these IL-4 overexpressing mice. Finally, a subset of patients (31%) with steroid-sensitive nephrotic syndrome possessed glomerular STAT6 activation.

Conclusions These findings suggest a potential explanation for the utility of immunosuppression and more targeted anti-B cell therapy with rituximab in the treatment of steroid-sensitive nephrotic syndromes. These results support the role of IL-4 in human nephrotic syndromes and represents a novel therapeutic target.

Disclosure of Interest A. Kim Grant/research support from: Rheumatology Research Foundation, Kypha Inc., S. Akilesh: None declared, A. Koziell: None declared, B. Saunders: None declared, S. Jain Grant/research support from: NIDDK/NIH, J. Hodgin Grant/research support from: NephCure/American Society of Nephrology, B. Zinselmeyer: None declared, T. Stappenback: None declared, J. Miner Grant/research support from: NIDDK/NIH, A. Shaw Employee of: Genentech, Inc.

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