Abstract: TH-PO0410
A Metabolic-Purinergic Survival Axis in B Cells Is a Therapeutic Target in Lupus Nephritis
Session Information
- Glomerular Diseases: Autoimmune Diseases
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Ishaq, Tayyaba, Yale University, New Haven, Connecticut, United States
- Chernova, Irene, Yale University, New Haven, Connecticut, United States
Background
Lupus nephritis (LN) is characterized by immune cell infiltration and glomerular injury, with intrarenal lymphocytes correlating with disease severity. We previously investigated the mechanisms involved in intrarenal B lymphocyte survival and showed that blocking the ion transporter Na-K-ATPase (NKA) or deleting its auxiliary subunit γ (gNKA; Fxyd2) reduces intrarenal B cells and improves proteinuria, without affecting other immune lineages. Here we set out to mechanistically define how NKA promotes B cell survival.
Because NKA is a major cellular consumer of ATP, we hypothesized that it regulates B cell survival through control of ATP consumption. ATP can function not only as an intracellular energy source, but also as an extracellular signaling molecule via purinergic receptors. We therefore investigated how NKA-dependent ATP utilization shapes intracellular and extracellular ATP (iATP, eATP) pools and downstream eATP signaling, and how these processes influence B cell survival.
Methods
We used lupus-prone MRLlpr mice intact or deficient for gNKA and performed in vitro and in vivo pharmacologic perturbations of ATP hydrolysis and purinergic signaling. NKA-mediated ATP hydrolysis, [iATP] and [eATP] were quantified and in vitro B cell survival and in vivo B cell numbers and proteinuria were assessed following modulation of [ATP] and eATP pathway signaling.
Results
Loss of gNKA increased NKA-mediated ATP hydrolysis, resulting in reduced [iATP] and [eATP] and a cell-intrinsic B cell survival defect. Surprisingly, iATP depletion did not explain the survival phenotype, as it was not associated with major downstream signaling or transcriptional changes. In contrast, modulation of eATP availability directly altered B cell survival: increasing eATP improved survival, whereas eATP degradation worsened survival. This eATP-dependent survival was mediated via purinergic receptors P2RX4 and P2RX7 with receptor inhibition reducing B cell survival. In vivo, P2RX4 inhibition resulted in >50% depletion of intrarenal B cells in lupus-prone mice and was associated with improved proteinuria.
Conclusion
We define a novel ion transporter-ATP consumption-eATP signaling survival axis in B cells in which gNKA regulates ATP consumption altering downstream eATP availability and signaling. Targeting this pathway in lupus results in selective depletion of intrarenal B cells and improvement of proteinuria in lupus nephritis.
Funding
- NIDDK Support