The Ion Transporter Na+-K+-ATPase Enables Pathological B Cell Survival in the Kidney Microenvironment of Lupus Nephritis
Year: 2022
Type: article
Abstract: 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 MRLlpr 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 MRLlpr 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. Conclusions: 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 - National Institutes of Health grant R37 AR40072, National Institutes of Health grant R01 AI152443, Private Foundation Support
Authors: Irene Chernova, Joseph Craft
Institution: Yale University
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4397046458