Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Bone marrow-derived immature myeloid cells are a main source of circulating suPAR contributing to proteinuric kidney disease


Excess levels of protein in urine (proteinuria) is a hallmark of kidney disease that typically occurs in conjunction with diabetes, hypertension, gene mutations, toxins or infections but may also be of unknown cause (idiopathic)1. Systemic soluble urokinase plasminogen activator receptor (suPAR) is a circulating factor implicated in the onset and progression of chronic kidney disease (CKD)2, such as focal segmental glomerulosclerosis (FSGS)3,4. The cellular source(s) of elevated suPAR associated with future and progressing kidney disease is unclear, but is likely extra-renal, as the pathological uPAR is circulating and FSGS can recur even after a damaged kidney is replaced with a healthy donor organ. Here we report that bone marrow (BM) Gr-1lo immature myeloid cells are responsible for the elevated, pathological levels of suPAR, as evidenced by BM chimera and BM ablation and cell transfer studies. A marked increase of Gr-1lo myeloid cells was commonly found in the BM of proteinuric animals having high suPAR, and these cells efficiently transmit proteinuria when transferred to healthy mice. In accordance with the results seen in suPAR-associated proteinuric animal models, in which kidney damage is caused not by local podocyte-selective injury but more likely by systemic insults, a humanized xenograft model of FSGS resulted in an expansion of Gr-1lo cells in the BM, leading to high plasma suPAR and proteinuric kidney disease. Together, these results identify suPAR as a functional connection between the BM and the kidney, and they implicate BM immature myeloid cells as a key contributor to glomerular dysfunction.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Hematopoietic cells are sufficient for suPAR-associated proteinuria.
Figure 2: Expansion of Gr-1lo BM cells is involved in suPAR-associated proteinuria.
Figure 3: BM immature myeloid cells have an ability to transfer disease.
Figure 4: hFSGS CD34+ cells induce suPAR-associated proteinuria in mice.

Accession codes

Primary accessions

NCBI Reference Sequence


  1. Fogo, A.B. Mechanisms of progression of chronic kidney disease. Pediatr. Nephrol. 22, 2011–2022 (2007).

    Article  Google Scholar 

  2. Hayek, S.S. et al. Soluble urokinase receptor and chronic kidney disease. N. Engl. J. Med. 373, 1916–1925 (2015).

    CAS  Article  Google Scholar 

  3. Wei, C. et al. Modification of kidney barrier function by the urokinase receptor. Nat. Med. 14, 55–63 (2008).

    CAS  Article  Google Scholar 

  4. Wei, C. et al. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat. Med. 17, 952–960 (2011).

    CAS  Article  Google Scholar 

  5. Cravedi, P., Kopp, J.B. & Remuzzi, G. Recent progress in the pathophysiology and treatment of FSGS recurrence. Am. J. Transplant. 13, 266–274 (2013).

    CAS  Article  Google Scholar 

  6. Winn, M.P. et al. A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science 308, 1801–1804 (2005).

    CAS  Article  Google Scholar 

  7. D'Agati, V.D., Kaskel, F.J. & Falk, R.J. Focal segmental glomerulosclerosis. N. Engl. J. Med. 365, 2398–2411 (2011).

    CAS  Article  Google Scholar 

  8. Kitiyakara, C., Eggers, P. & Kopp, J.B. Twenty-one-year trend in ESRD due to focal segmental glomerulosclerosis in the United States. Am. J. Kidney Dis. 44, 815–825 (2004).

    Article  Google Scholar 

  9. Fogo, A.B. Causes and pathogenesis of focal segmental glomerulosclerosis. Nat. Rev. Nephrol. 11, 76–87 (2015).

    CAS  Article  Google Scholar 

  10. Gallon, L., Leventhal, J., Skaro, A., Kanwar, Y. & Alvarado, A. Resolution of recurrent focal segmental glomerulosclerosis after retransplantation. N. Engl. J. Med. 366, 1648–1649 (2012).

    CAS  Article  Google Scholar 

  11. McCarthy, E.T., Sharma, M. & Savin, V.J. Circulating permeability factors in idiopathic nephrotic syndrome and focal segmental glomerulosclerosis. Clin. J. Am. Soc. Nephrol. 5, 2115–2121 (2010).

    Article  Google Scholar 

  12. Savin, V.J. et al. Circulating factor associated with increased glomerular permeability to albumin in recurrent focal segmental glomerulosclerosis. N. Engl. J. Med. 334, 878–883 (1996).

    CAS  Article  Google Scholar 

  13. Thunø, M., Macho, B. & Eugen-Olsen, J. suPAR: the molecular crystal ball. Dis. Markers 27, 157–172 (2009).

    Article  Google Scholar 

  14. Blasi, F. & Carmeliet, P. uPAR: a versatile signalling orchestrator. Nat. Rev. Mol. Cell Biol. 3, 932–943 (2002).

    CAS  Article  Google Scholar 

  15. Smith, H.W. & Marshall, C.J. Regulation of cell signalling by uPAR. Nat. Rev. Mol. Cell Biol. 11, 23–36 (2010).

    CAS  Article  Google Scholar 

  16. Faul, C. et al. The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat. Med. 14, 931–938 (2008).

    CAS  Article  Google Scholar 

  17. Reiser, J. et al. Induction of B7-1 in podocytes is associated with nephrotic syndrome. J. Clin. Invest. 113, 1390–1397 (2004).

    CAS  Article  Google Scholar 

  18. Bertelli, R. et al. LPS nephropathy in mice is ameliorated by IL-2 independently of regulatory T cells activity. PLoS One 9, e111285 (2014).

    Article  Google Scholar 

  19. Shultz, L.D. et al. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. J. Immunol. 174, 6477–6489 (2005).

    CAS  Article  Google Scholar 

  20. Basu, S., Hodgson, G., Katz, M. & Dunn, A.R. Evaluation of role of G-CSF in the production, survival, and release of neutrophils from bone marrow into circulation. Blood 100, 854–861 (2002).

    CAS  Article  Google Scholar 

  21. Liu, F., Wu, H.Y., Wesselschmidt, R., Kornaga, T. & Link, D.C. Impaired production and increased apoptosis of neutrophils in granulocyte colony-stimulating factor receptor-deficient mice. Immunity 5, 491–501 (1996).

    CAS  Article  Google Scholar 

  22. Kopp, J.B. et al. Transgenic mice with increased plasma levels of TGF-beta 1 develop progressive renal disease. Lab. Invest. 74, 991–1003 (1996).

    CAS  PubMed  Google Scholar 

  23. Schiffer, M. et al. Apoptosis in podocytes induced by TGF-beta and Smad7. J. Clin. Invest. 108, 807–816 (2001).

    CAS  Article  Google Scholar 

  24. Kistler, A.D. et al. Transient receptor potential channel 6 (TRPC6) protects podocytes during complement-mediated glomerular disease. J. Biol. Chem. 288, 36598–36609 (2013).

    CAS  Article  Google Scholar 

  25. Hudkins, K.L. et al. BTBR Ob/Ob mutant mice model progressive diabetic nephropathy. J. Am. Soc. Nephrol. 21, 1533–1542 (2010).

    CAS  Article  Google Scholar 

  26. Yu, H. et al. Rac1 activation in podocytes induces rapid foot process effacement and proteinuria. Mol. Cell. Biol. 33, 4755–4764 (2013).

    CAS  Article  Google Scholar 

  27. Papeta, N. et al. Prkdc participates in mitochondrial genome maintenance and prevents Adriamycin-induced nephropathy in mice. J. Clin. Invest. 120, 4055–4064 (2010).

    CAS  Article  Google Scholar 

  28. Alfano, M. et al. Full-length soluble urokinase plasminogen activator receptor down-modulates nephrin expression in podocytes. Sci. Rep. 5, 13647 (2015).

    Article  Google Scholar 

  29. Cathelin, D. et al. Administration of recombinant soluble urokinase receptor per se is not sufficient to induce podocyte alterations and proteinuria in mice. J. Am. Soc. Nephrol. 25, 1662–1668 (2014).

    CAS  Article  Google Scholar 

  30. Spinale, J.M. et al. A reassessment of soluble urokinase-type plasminogen activator receptor in glomerular disease. Kidney Int. 87, 564–574 (2015).

    CAS  Article  Google Scholar 

  31. Delville, M. et al. A circulating antibody panel for pretransplant prediction of FSGS recurrence after kidney transplantation. Sci. Transl. Med. 6, 256ra136 (2014).

    Article  Google Scholar 

  32. Huang, J. et al. Urinary soluble urokinase receptor levels are elevated and pathogenic in patients with primary focal segmental glomerulosclerosis. BMC Med. 12, 81 (2014).

    CAS  Article  Google Scholar 

  33. Holmes, C. & Stanford, W.L. Concise review: stem cell antigen-1: expression, function, and enigma. Stem Cells 25, 1339–1347 (2007).

    CAS  Article  Google Scholar 

  34. Shi, X. et al. Toll-like receptor 4/stem cell antigen 1 signaling promotes hematopoietic precursor cell commitment to granulocyte development during the granulopoietic response to Escherichia coli bacteremia. Infect. Immun. 81, 2197–2205 (2013).

    CAS  Article  Google Scholar 

  35. Shultz, L.D., Brehm, M.A., Garcia-Martinez, J.V. & Greiner, D.L. Humanized mice for immune system investigation: progress, promise and challenges. Nat. Rev. Immunol. 12, 786–798 (2012).

    CAS  Article  Google Scholar 

  36. Brehm, M.A., Shultz, L.D. & Greiner, D.L. Humanized mouse models to study human diseases. Curr. Opin. Endocrinol. Diabetes Obes. 17, 120–125 (2010).

    Article  Google Scholar 

  37. Ito, R., Takahashi, T., Katano, I. & Ito, M. Current advances in humanized mouse models. Cell. Mol. Immunol. 9, 208–214 (2012).

    CAS  Article  Google Scholar 

  38. Sellier-Leclerc, A.L. et al. A humanized mouse model of idiopathic nephrotic syndrome suggests a pathogenic role for immature cells. J. Am. Soc. Nephrol. 18, 2732–2739 (2007).

    Article  Google Scholar 

  39. Niu, H. et al. The function of hematopoietic stem cells is altered by both genetic and inflammatory factors in lupus mice. Blood 121, 1986–1994 (2013).

    CAS  Article  Google Scholar 

  40. Zhao, J.L. et al. Conversion of danger signals into cytokine signals by hematopoietic stem and progenitor cells for regulation of stress-induced hematopoiesis. Cell Stem Cell 14, 445–459 (2014).

    CAS  Article  Google Scholar 

Download references


We thank A.S. Shaw (Washington University School of Medicine) for the Rac1 transgenic mice; S. Shankland (University of Washington) for providing the nephrotoxic serum (NTS); A. Finnegan (Rush University Medical Center) for reagents and advice; B. Samelko (née Tryniszewska) (Rush University Medical Center) for technical assistance; and S. Mangos (Rush University Medical Center) for help with manuscript revisions. This research was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) R01DK101350 (J.R.), R01DK106051 (J.R.), R01DK107984 (V.G.) and R01DK084195 (V.G.).

Author information

Authors and Affiliations



E.H. designed and performed experiments, and wrote the paper; I.F., J.L., and Y.C. performed animal experiments; N.J.T. generated electron micrographs; A.Z. and J.L. contributed to xenotransplantation experiment; C.W., M.T., S.W., V.P., S.S.H., C.O., M.B., V.G., S.S., D.B.S., and D.T.S. contributed to experiments; J.R. designed and supervised the study, and wrote the paper.

Corresponding author

Correspondence to Jochen Reiser.

Ethics declarations

Competing interests

E.H., C.W., S.S., and J.R. are inventors on pending and issued patents related to anti-proteinuric therapies. They stand to gain royalties from present and future commercialization. J.R. and S.S. are also co-founders and advisors to TRISAQ, a biotechnology company. The remaining authors report no conflicts.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–12 (PDF 18323 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hahm, E., Wei, C., Fernandez, I. et al. Bone marrow-derived immature myeloid cells are a main source of circulating suPAR contributing to proteinuric kidney disease. Nat Med 23, 100–106 (2017).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing