title: 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). 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-1loimmature 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-1lomyeloid 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-1locells 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.
authors.affiliation: Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Eunsil
authors.identifier: 0000-0002-0343-7473
authors.initials: E
authors.lastname: Hahm
authors.affiliation: Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Changli
authors.initials: C
authors.lastname: Wei
authors.affiliation: Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Isabel
authors.initials: I
authors.lastname: Fernandez
authors.affiliation: Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Tardi
authors.affiliation: Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Tracy
authors.affiliation: Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Shikha
authors.initials: S
authors.lastname: Wadhwani
authors.affiliation: Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Vasil
authors.initials: V
authors.lastname: Peev
authors.affiliation: 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.
authors.forename: Andrew
authors.initials: A
authors.lastname: Zloza
authors.affiliation: Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.|Department of Immunology/Microbiology, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Jevgenijs
authors.identifier: 0000-0002-1962-6703
authors.initials: J
authors.lastname: Lusciks
authors.affiliation: Division of Cardiology, Emory Clinical Cardiovascular Research Institute, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Salim S
authors.identifier: 0000-0003-0180-349X
authors.initials: SS
authors.lastname: Hayek
authors.affiliation: Division of Nephrology, Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: O'Connor
authors.affiliation: Division of Nephrology, Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Bitzer
authors.affiliation: Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Vineet
authors.identifier: 0000-0001-6987-2550
authors.initials: V
authors.lastname: Gupta
authors.affiliation: Division of Nephrology, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
authors.forename: Sanja
authors.initials: S
authors.lastname: Sever
authors.affiliation: 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.
authors.forename: David B
authors.initials: DB
authors.lastname: Sykes
authors.affiliation: 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.
authors.forename: David T
authors.initials: DT
authors.lastname: Scadden
authors.affiliation: Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Jochen
authors.initials: J
authors.lastname: Reiser
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001854:Bone Marrow Cells; D004195:Disease Models, Animal; D005923:Glomerulosclerosis, Focal Segmental / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000378:metabolism*; D011507:Proteinuria / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism*; D051436:Renal Insufficiency, Chronic / Q000378:metabolism*
chemical_list: C524899:Plaur protein, mouse; D055293:Receptors, Urokinase Plasminogen Activator