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Abstract: SA-PO976

Altered Bone Marrow Myelopoiesis Contributes to Glomerular Dysfunction

Session Information

Category: Glomerular Diseases

  • 1403 Podocyte Biology

Authors

  • Spear, Ryan, Rush University Medical Center, Chicago, Illinois, United States
  • Jimenez Uribe, Alexis P., Rush University Medical Center, Chicago, Illinois, United States
  • Cao, Yanxia, Rush University Medical Center, Chicago, Illinois, United States
  • Mangos, Steve, Rush University Medical Center, Chicago, Illinois, United States
  • Vincenti, Flavio, University of California San Francisco, San Francisco, California, United States
  • Reiser, Jochen, Rush University Medical Center, Chicago, Illinois, United States
  • Hahm, Eunsil, Rush University Medical Center, Chicago, Illinois, United States
Background

Myeloid-biased hematopoiesis is observed in disease conditions associated with CKD, including infection, chronic inflammation, diabetes, CVD, and aging. Despite identifying immature myeloid cells (MCs) in the bone marrow (BM) as a significant contributor to renal injury in mice, the link between BM and kidney function in humans is not yet determined. Here, we tested if inflammatory signals alter BM myelopoiesis leading to glomerular dysfunction.

Methods

Flow cytometry (FC) was performed to evaluate the immunophenotyping of BM cells from CKD patients and healthy individuals, as well as human MCs differentiated in vitro. Bioenergetic and epigenetic changes in monocytes were assessed by Seahorse and ATAC-seq. Secretome analyses were performed using ELISA multiplex cytokine assay and FC staining. We assessed the impact of functionally altered MCs and their soluble factors to podocyte structure and filtration function by conducting an immunofluorescence assay on cultured podocyte and two different animal models.

Results

CKD patients exhibited increased levels of TNFα and suPAR in their BM and a myeloid-biased hematopoiesis, with an increase in inflammatory monocytes expressing uPAR. In vitro assays revealed that TNFα can alter myelopoiesis by skewing hematopoietic stem cell (HSC) differentiation towards monocytic lineage cells, leading to functional changes in the resultant monocytes. These TNFα-driven monocyte subsets exhibited increased uPAR expression and suPAR secretion, metabolic activity, and production of proinflammatory cytokines. Also, TNFα increased chromatin accessibility to genes for proinflammatory cytokines, metabolic activity, and those involved in inflammation signaling pathways, as evidenced by ATACseq. The soluble factors secreted by TNFα-driven MCs caused cytoskeletal rearrangement in cultured podocytes and filtration dysfunction in a transgenic zebrafish model. Mice injected with TNFα and IFNγ exhibited suPAR-associated glomerular dysfunction, demonstrated by albuminuria, and an increase in BUN levels, suPAR levels, and uPAR-expressing BM MCs.

Conclusion

This study reveals, for the first time, that TNFα contributes to renal injury by altering BM myelopoiesis and promoting the development of metabolically and epigenetically reprogrammed monocyte subsets that secrete soluble permeability factors and cytokines.

Funding

  • NIDDK Support