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Nat Med. 2017 Jan;23(1):100-106. doi: 10.1038/nm.4242. Epub 2016 Dec 12.

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

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Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
Department of Immunology/Microbiology, Rush University Medical Center, Chicago, Illinois, USA.
Division of Surgical Oncology Research, Section of Surgical Oncology, Rutgers Cancer Institute of New Jersey, and Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
Division of Cardiology, Emory Clinical Cardiovascular Research Institute, Emory University School of Medicine, Atlanta, Georgia, USA.
Division of Nephrology, Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Division of Nephrology, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Stem Cell Institute and the Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.


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). Systemic soluble urokinase plasminogen activator receptor (suPAR) is a circulating factor implicated in the onset and progression of chronic kidney disease (CKD), such as focal segmental glomerulosclerosis (FSGS). 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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