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Abstract: PO1770

Enhanced Na-K-ATPase Expression Mediates B-Cell Survival in Lupus Kidneys

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Chernova, Irene, Yale University School of Medicine, New Haven, Connecticut, United States
  • Craft, Joseph, Yale University School of Medicine, New Haven, Connecticut, United States
Background

Systemic lupus erythematosus (SLE, lupus) is a multi-organ autoimmune disease characterized by antibody deposition in target organs, including the kidney. Kidneys of affected patients are characterized by lymphocytic infiltrates that correlate with tissue damage and disease severity. The kidneys are also characterized by a high salt environment not found elsewhere in the body. Thus, infiltrating lymphocytes are presented with the unique challenge of surviving in a high salinity environment which may define their phenotype and function. We now describe the molecular mechanisms utilized by immune cells when faced with this hypertonic microenvironment.

Methods

We utilized lupus-prone (MRLlpr) and wildtype (C57BL/6) mice and renal biopsy samples from lupus nephritis patients for this study. B cells from mice were cultured in vitrounder standard versus high salt conditions. Kidney immune cell subsets were identified using flow cytometry and immunofluorescence techniques.

Results

B cells from lupus-prone (MRLlpr) mice have enhanced survival when exposed in vitro to a high salt environment, compared to cells from control, non-autoimmune mice. The salt transporter Na-K-ATPase, and specifically its gamma subunit Fxyd2, is upregulated in the kidney and is necessary for kidney epithelial (tubular) cell survival under high salt conditions. We hypothesized that infiltrating lymphocytes also utilize Na-K-ATPase upregulation to survive in the hypertonic environment of the kidney. We found high expression of Na-K-ATPase alpha and gamma subunits on kidney-localized B cells of lupus-prone mice and high gamma subunit expression in B cells from human lupus kidney biopsies. Inhibition of Na-K-ATPase activity with a small molecule inhibitor ouabain led to increased cell death when lupus-prone B cells, but not control B cells, were cultured in high salt conditions, suggesting a role for Na-K-ATPase in the enhanced survival of MRLlpr B cells in high salt. In vivo treatment of MRLlpr mice with ouabain depleted renal-infiltrating B cells, but not T cells. MRLlprmice lacking the gamma subunit of Na-K-ATPase appear to phenocopy the ouabain-treated mice in preliminary analyses.

Conclusion

These studies identify a novel role for Na-K-ATPase in B cell survival in the hypertonic renal microenvironment and suggest it is a potential therapeutic target in lupus nephritis.

Funding

  • Other NIH Support