Bone marrow-derived immature myeloid cells are a main source of circulating suPAR contributing to proteinuric kidney disease.
Eunsil HahmChangli WeiIsabel FernandezJing LiNicholas J TardiMelissa TracyShikha WadhwaniYanxia CaoVasil PeevAndrew ZlozaJevgenijs LusciksSalim Salim HayekChristopher O'ConnorMarkus BitzerVineet GuptaSanja SeverDavid B SykesDavid T ScaddenJochen ReiserPublished in: Nature medicine (2016)
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.
Keyphrases
- induced apoptosis
- bone marrow
- cell cycle arrest
- chronic kidney disease
- endoplasmic reticulum stress
- acute myeloid leukemia
- dendritic cells
- blood pressure
- oxidative stress
- mesenchymal stem cells
- type diabetes
- cell death
- cell proliferation
- small molecule
- insulin resistance
- atrial fibrillation
- end stage renal disease
- endothelial cells
- amino acid
- peritoneal dialysis
- pi k akt
- drug induced
- monoclonal antibody