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

Abstract

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.

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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.

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Acknowledgements

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.).

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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.

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Correspondence to Jochen Reiser.

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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.

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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). https://doi.org/10.1038/nm.4242

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