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Abstract: FR-OR46

Soluble Flt1 Binds to Anti-Inflammatory Macrophages in the Kidney

Session Information

Category: Pathology and Lab Medicine

  • 1600 Pathology and Lab Medicine


  • Van Aanhold, Cleo Christina lioe, Leids Universitair Medisch Centrum, Leiden, Zuid-Holland, Netherlands
  • Landman, Lisa, Leids Universitair Medisch Centrum, Leiden, Zuid-Holland, Netherlands
  • Sardana, Samiksha, Universiteit Utrecht, Utrecht, Utrecht, Netherlands
  • Dijkstra, Kyra L., Leids Universitair Medisch Centrum, Leiden, Zuid-Holland, Netherlands
  • Bruijn, Jan A., Leids Universitair Medisch Centrum, Leiden, Zuid-Holland, Netherlands
  • van Kooten, Cees, Leids Universitair Medisch Centrum, Leiden, Zuid-Holland, Netherlands
  • Baelde, Hans J., Leids Universitair Medisch Centrum, Leiden, Zuid-Holland, Netherlands

Soluble Flt1 (sFlt1), a decoy receptor of VEGF ligands, is a key regulator of angiogenesis. High systemic levels of sFlt1 have been linked to the pathogenesis of preeclampsia. However, we have previously reported that treatment with low concentrations of sFlt1 ameliorates kidney damage and inflammation. Specifically, sFlt1 targets macrophages, suggesting that sFlt1 has nephroprotective immunomodulating effects. Here, we studied the presence of sFlt1 in human kidney diseases and investigated the expression and direct binding of sFlt1 to macrophages.


Renal biopsies of patients with various kidney diseases (IgA, LN, DN, FSGS, MCD) and pre-transplant control biopsies were stained for sFlt1, CD163 and CD68. Cultured macrophages were incubated with increasing concentrations of sFlt1-His, after which membrane binding was measured using flow cytometry. For this, THP-1 monocytes were differentiated with PMA and activated with IFN-γ+LPS or IL-4; primary macrophages were differentiated using GM-CSF or M-CSF.


A patchy pattern of sFlt1 staining colocalizes with CD163/CD68-positive cells in tubulointerstitial areas and with CD68-positive cells in glomeruli. No quantitative differences in renal sFlt1 levels were observed in patients with kidney disease and controls. Flow cytometric analysis revealed that sFlt1 binds to PMA-differentiated THP-1 macrophages but does not bind to THP-1 monocytes. Activation with IFN-γ and LPS decreases sFlt1 binding to THP-1 macrophages. However, IL-4 activation of THP-1 macrophages strongly increases membrane sFlt1 binding. Furthermore, IL-4 activation upregulates sFlt1 mRNA expression in THP-1 macrophages. In primary macrophages, sFlt1 binding was higher in macrophages differentiated with GM-CSF compared to M-CSF.


Our results suggest that sFlt1, while typically associated with angiogenesis, binds to anti-inflammatory macrophages in the human kidney. Alternative activation of macrophages by IL-4 strongly induces sFlt1 production and increases direct binding of sFlt1 to the cell surface membrane. We infer that sFlt1 functions as an autocrine stimulus of anti-inflammatory macrophages, independent of its antiangiogenic properties. Since anti-inflammatory macrophages mediate repair after kidney injury, our work suggests the potential of sFlt1 as a therapeutic tool.