Department of Medicine, Miller School of Medicine, University of Miami, Miami, Florida, USA.
Nat Med. 2011 Jul 31;17(8):952-60. doi: 10.1038/nm.2411.
Focal segmental glomerulosclerosis (FSGS) is a cause of proteinuric kidney disease, compromising both native and transplanted kidneys. Treatment is limited because of a complex pathogenesis, including unknown serum factors. Here we report that serum soluble urokinase receptor (suPAR) is elevated in two-thirds of subjects with primary FSGS, but not in people with other glomerular diseases. We further find that a higher concentration of suPAR before transplantation underlies an increased risk for recurrence of FSGS after transplantation. Using three mouse models, we explore the effects of suPAR on kidney function and morphology. We show that circulating suPAR activates podocyte β(3) integrin in both native and grafted kidneys, causing foot process effacement, proteinuria and FSGS-like glomerulopathy. Our findings suggest that the renal disease only develops when suPAR sufficiently activates podocyte β(3) integrin. Thus, the disease can be abrogated by lowering serum suPAR concentrations through plasmapheresis, or by interfering with the suPAR-β(3) integrin interaction through antibodies and small molecules targeting either uPAR or β(3) integrin. Our study identifies serum suPAR as a circulating factor that may cause FSGS.
局灶节段性肾小球硬化症（FSGS）是一种导致蛋白尿性肾病的病因，无论是在原生肾脏还是移植肾脏中都会发生。由于发病机制复杂，包括未知的血清因子，因此治疗方法受到限制。在这里，我们报告称，在三分之二的原发性 FSGS 患者中，血清可溶性尿激酶受体（suPAR）升高，但在其他肾小球疾病患者中则没有。我们进一步发现，移植前 suPAR 浓度较高会增加移植后 FSGS 复发的风险。使用三种小鼠模型，我们研究了 suPAR 对肾脏功能和形态的影响。我们表明，循环 suPAR 可激活原生和移植肾脏中的足细胞β(3)整合素，导致足突融合、蛋白尿和 FSGS 样肾小球病。我们的研究结果表明，只有当 suPAR 充分激活足细胞β(3)整合素时，肾脏疾病才会发展。因此，通过血浆置换降低血清 suPAR 浓度，或通过针对 uPAR 或β(3)整合素的抗体和小分子干扰 suPAR-β(3)整合素相互作用，可阻断疾病的发生。本研究确定血清 suPAR 是一种可能导致 FSGS 的循环因子。
