Bone marrow-derived immature myeloid cells are a main source of circulating suPAR contributing to proteinuric kidney disease.
Bone marrow-derived immature myeloid cells are a main source of circulating suPAR contributing to proteinuric kidney disease.
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DOI：
10.1038/nm.4242
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发表时间：
2017-01
期刊：
影响因子：
82.9
通讯作者：
Reiser J
中科院分区：
文献类型：
--
作者：
Hahm E;Wei C;Fernandez I;Li J;Tardi NJ;Tracy M;Wadhwani S;Cao Y;Peev V;Zloza A;Lusciks J;Hayek SS;O'Connor C;Bitzer M;Gupta V;Sever S;Sykes DB;Scadden DT;Reiser J
尿液中蛋白质水平过高（蛋白尿）是肾脏疾病的标志，通常与糖尿病，高血压，基因突变，毒素或感染有关，但也可能是未知原因（特发性）。系统性可溶性尿激酶纤溶酶原激活物受体（suPAR）是一种与慢性肾脏疾病（CKD）如局灶节段性肾小球硬化（FSGS）的发生和进展有关的循环因子。与未来和进展性肾脏疾病相关的suPAR升高的细胞来源尚不清楚，但可能是肾外的，因为病理性uPAR正在循环，即使在受损肾脏被健康供体器官替代后，FSGS也可能复发。在这里，我们报告说，骨髓（BM）Gr-1 LO不成熟的髓系细胞负责升高，病理水平的suPAR，证明了BM嵌合体和BM消融和细胞转移的研究。在具有高suPAR的蛋白尿动物的BM中通常发现Gr-1 lo髓样细胞的显著增加，并且当转移到健康小鼠时，这些细胞有效地传递蛋白尿。根据在suPAR相关蛋白尿动物模型中观察到的结果，其中肾损伤不是由局部足细胞选择性损伤引起的，而是更可能由全身性损伤引起的，FSGS的人源化异种移植模型导致BM中Gr-1 lo细胞的扩增，导致高血浆suPAR和蛋白尿性肾病。总之，这些结果将suPAR鉴定为BM和肾脏之间的功能性连接，并且它们暗示BM未成熟髓样细胞是肾小球功能障碍的关键贡献者。
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.