Abstract: FR-OR40
The "TNFa-suPAR" Axis Links Bone Marrow Alterations to Kidney Dysfunction
Session Information
- Glomerular Diseases: Mechanisms and More
October 25, 2024 | Location: Room 1, Convention Center
Abstract Time: 05:00 PM - 05:10 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Jimenez Uribe, Alexis P., Rush University, Chicago, Illinois, United States
- Spear, Ryan, Rush University, Chicago, Illinois, United States
- Cao, Yanxia, Rush University, Chicago, Illinois, United States
- Mangos, Steve, Rush University, Chicago, Illinois, United States
- Reiser, Jochen, The University of Texas Medical Branch at Galveston Development Office, Galveston, Texas, United States
- Hahm, Eunsil, Rush University, Chicago, Illinois, United States
Background
Previous study identified bone marrow (BM)-derived immature myeloid cells as the source of soluble urokinase plasminogen activator receptor (suPAR), a key inflammatory mediator causing glomerular damage and proteinuria in mice. However, the factor driving the expansion of these pathogenic myeloid cells and suPAR increase remains unknown. Preliminary data show elevated TNFα and suPAR levels in the BM of CKD patients with altered hematopoiesis. This study tests the hypothesis that TNFa induces BM alterations and subsequent suPAR increase, thereby contributing to the renal dysfunction
Methods
TNFa levels were measured from three proteinuric animal models; TGFb-Tg mice (progressive glomerulosclerosis), nephrotoxic serum (NTS)-injected mice (glomerulonephritis), and LPS-injected mice (acute kidney injury). Functional in vivo tests included TNFa blockade, suPAR-deficient mice, and TNFa injection alone or with IFNg. In vitro myelopoiesis assays were performed using human hematopoietic stem cells or HL-60 promyelocytic cell line, with or without TNFa. Immunophenotyping, secretome analysis, and metabolic evaluation were conducted using multiparametric flow cytometry, multiplex, ELISA, and Seahorse assays
Results
Our results revealed elevated TNFa levels in three proteinuric animal models characterized by high suPAR and expanded immature myeloid cells in the BM. Blocking TNFa reduced both proteinuria and suPAR levels. TNFa alone was not enough to cause renal injury without suPAR or active myelopoiesis. However, when co-injected with IFNg (a key cytokine for myelopoiesis), TNFa triggered significant myeloid cell expansion, increased suPAR levels, and proteinuria in mice. In vitro myelopoiesis assays demonstrated that TNFa attenuates granulocytic lineage development, favoring monocytic lineage differentiation. Additionally, TNFa enriched a glycolytic and oxidative metabolic phenotype in monocytic cells, enhancing suPAR and proinflammatory cytokines secretion.
Conclusion
Our study suggests that renal function is regulated by bone marrow alterations through the ‘TNFa-suPAR’ axis, resembling findings from CKD patients and mouse models of proteinuria. This implies that the ‘TNFa-suPAR’ axis serves as a common key pathway linking bone marrow alterations to renal dysfunction.
Funding
- NIDDK Support