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Kidney Week

Abstract: TH-PO105

suPAR Inflames Kidneys With T Cells and Aggravates Septic AKI

Session Information

  • AKI: Mechanisms - I
    November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Nusshag, Christian, Ruprecht Karls Universitat Heidelberg, Heidelberg, Baden-Württemberg, Germany
  • Wei, David Changli, Rush University Medical Center, Chicago, Illinois, United States
  • Hahm, Eunsil, Rush University Medical Center, Chicago, Illinois, United States
  • Hayek, Salim, University of Michigan, Ann Arbor, Michigan, United States
  • Li, Jing, Rush University Medical Center, Chicago, Illinois, United States
  • Kälble, Florian, Ruprecht Karls Universitat Heidelberg, Heidelberg, Baden-Württemberg, Germany
  • Speer, Claudius, Ruprecht Karls Universitat Heidelberg, Heidelberg, Baden-Württemberg, Germany
  • Eugen-Olsen, Jesper, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
  • Krautkrämer, Ellen, Ruprecht Karls Universitat Heidelberg, Heidelberg, Baden-Württemberg, Germany
  • Zeier, Martin G., Ruprecht Karls Universitat Heidelberg, Heidelberg, Baden-Württemberg, Germany
  • Morath, Christian, Ruprecht Karls Universitat Heidelberg, Heidelberg, Baden-Württemberg, Germany
  • Brenner, Thorsten, Universitatsklinikum Essen, Essen, Nordrhein-Westfalen, Germany
  • Reiser, Jochen, Rush University Medical Center, Chicago, Illinois, United States
Background

The soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived glycoprotein implicated in the pathogenesis of acute kidney injury (AKI). Sepsis is a strong inducer of plasma suPAR levels and a known contributor to the development of AKI. We hypothesized that suPAR is involved in the pathophysiology of sepsis-related AKI.

Methods

We used a polymicrobial model of sepsis (Cecal Slurry [CS] vs. Glycerol [GLY]) in wild-type (WT), uPAR knockout (KO, suPAR deficient), and transgenic suPAR-overexpressing (OE) mice. We compared measures of kidney function, tissue damage, and tissue inflammation in septic and untreated mice. Kidney tissue inflammation was quantified by kidney flow cytometry, immunohistostaining, and kidney luminex assay.

Results

Kidneys from untreated OE mice expressed high levels of interleukin-16 (IL-16) and C-C motif chemokine ligand 3 (CCL3); both involved in cell-mediated kidney injury and potent chemo-attractants for T and NK cells. Consistent with this expression pattern, we found significantly increased numbers of kidney T and NK cells in untreated OE mice, equaling numbers observed in septic WT mice. Further, high plasma suPAR aggravated sepsis-induced ultrastructural kidney damage, cellular apoptosis and kidney function impairment after 24h of sepsis. In contrast, KO mice showed a strong protective effect against AKI. Kaplan-Meier analysis revealed a survival benefit of KO over OE mice (87% vs. 50%, p=0.033). The composition of kidney immune cells in sepsis was strongly influenced by varying suPAR plasma levels. Especially, numbers of kidney T cells were strongly linked to the extent of systemic suPAR elevation and kidney function impairment, with significant higher numbers in septic OE mice compared to septic WT and KO mice.

Conclusion

suPAR inflames the kidney with T cells potentially via local upregulation of IL-16 and CCL3. “SuPAR inflamed” kidneys react with increased kidney injury in sepsis which can potentially be improved by deleting suPAR. These findings hold great potential for new therapeutic strategies.