The Effect of Sodium (Na+) on Kidney B cells in Lupus Nephritis

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Project Summary Lupus nephritis is the kidney manifestation of the autoimmune disease systemic lupus erythematosus (SLE, lupus); 10% of those afflicted progress to end stage kidney disease. Lupus nephritis kidneys are characterized by a profound lymphocytic infiltrate and the degree of infiltrate, including B lymphocytes specifically, correlates with tissue damage and disease severity. Kidneys are also characterized by axial concentration gradients of sodium (Na+), up to 2-fold higher than serum. Thus the inimical kidney environment presents unique survival challenges for infiltrating lymphocytes that may shape their phenotype and function. The function of intrarenal B cells and the pathways they employ to adapt to the hostile kidney environment remain uncharacterized. My preliminary data demonstrate that B cells from lupus-prone mice exhibit enhanced survival when exposed to high Na+ ex vivo as compared to wildtype mice. This effect was mediated by high expression of sodium potassium ATPase (Na+-K+-ATPase, NKA), a key regulator of cellular ionic balance. I have also shown that kidney-infiltrating B cells in murine lupus adapted to elevated [Na+] and that the expression of in vivo NKA correlated with the ability of infiltrating B cells to persist in the kidney. Pharmacological inhibition of NKA and genetic knockout of the NKA g subunit, the latter not previously known to be expressed in B cells, resulted in reduced kidney B cell infiltration and amelioration of proteinuria. B cells in renal biopsies of SLE patients also expressed more NKA than intrarenal T cells, suggesting the same NKA-regulated B cell survival pathway is operative in human SLE nephritis. How Na+ affects cell death pathways and whether it regulates B cell function, such as antibody or cytokine production, is unknown. I hypothesize that Na+ modulates intrarenal B cell death pathways and function, dissection of which will augment understanding of lupus nephritis pathogenesis. In Aim 1, I will investigate death pathways that lupus versus healthy control B cells undergo when exposed to high Na+ ex vivo. In Aim 2, I will assess B cell function upon alteration of kidney Na+ environment in mice while in Aim 3 I will utilize in situ imaging to define the functional landscape of these pathogenic cells in human SLE nephritis biopsies. Together these studies will help identify kidney-specific targets for the treatment of SLE nephritis. The candidate for this award is a physician-scientist with dual expertise in nephrology and immunology. Her long-term goals are to be an independent academic researcher with a focus on autoimmune kidney disease and lymphocyte-ion interactions. This award would allow the candidate to receive exceptional mentorship from the departments of Immunobiology and Nephrology at Yale University School of Medicine, a premier research institution. A comprehensive career development plan with coursework in bioinformatics and statistics, acquisition of RNA hybridization and imaging techniques and professional development focused on grant and manuscript preparation is designed to promote the candidate’s career goals and will be facilitated by this award.