Kidney Week

Abstract: FR-PO597

The Ion Transporter Na+-K+-ATPase Enables Pathological B Cell Survival in the Kidney Microenvironment of Lupus Nephritis

Session Information

• Glomerular Diseases: Lupus and Vasculitis
  November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1302 Glomerular Diseases: Immunology and Inflammation

Authors

• Chernova, Irene, Yale University School of Medicine Department of Internal Medicine, New Haven, Connecticut, United States

Irene Chernova,

• Craft, Joseph, Yale University School of Medicine Department of Internal Medicine, New Haven, Connecticut, United States

Joseph Craft,

Background

The kidney is a unique microenvironment characterized by high sodium concentrations [Na⁺], yet susceptible to infiltration by lymphocytes in autoimmune diseases such as systemic lupus erythematosus. The mechanisms used by infiltrating lymphocytes to survive the high Na⁺ environment of the kidney are not known.

Methods

We investigated how B cells from lupus-prone MRL^lpr mice respond to Na⁺ stress using cell culture and water deprivation experiments. The role of sodium potassium ATPase (Na⁺-K⁺-ATPase, NKA) in intrarenal B cell survival was investigated using small molecule studies, the generation of lupus-prone mice missing an NKA subunit and bone marrow (BM) chimera studies. Key findings regarding NKA expression were validated in additional murine lupus models and human lupus nephritis biopsies.

Results

We show that kidney infiltrating B cells in lupus adapt to elevated [Na⁺] and that NKA expression correlates with the ability of infiltrating cells to persist in the kidney. Compared to MRL^lpr B cells, B cells from non-autoimmune mice had lower NKA expression, evidenced increased apoptosis when exposed to high [Na⁺] and did not take up residence in the kidney. NKA expression was induced by high [Na⁺] in vitro and was increased in kidney, as compared to spleen, B cells in several lupus-prone mouse strains. Pharmacological inhibition of NKA and genetic knockout of the NKA γ subunit, previously not known to be expressed in B cells, resulted in reduced kidney B cell infiltration and amelioration of proteinuria without affecting systemic B cells or other intrarenal immune cell populations. The γNKA deletion effect was B cell-intrinsic as confirmed by BM chimera studies. B cells in biopsies of lupus nephritis patients also evidenced higher expression of NKA and its γ subunit than T cells.

Conclusion

We show that kidney-infiltrating B cells in lupus initiate a tissue adaption program in response to Na⁺ stress and identify Na⁺-K⁺-ATPase as a potential organ-specific therapeutic target in lupus nephritis.

Funding

• Other NIH Support