Huang Jing, Liu Gang, Zhang Yi-miao, Cui Zhao, Wang Fang, Liu Xiao-jing, Chu Rong, Zhao Ming-hui
Renal Division, Peking University First Hospital, Beijing, PR China.
BMC Med. 2014 May 20;12:81. doi: 10.1186/1741-7015-12-81.
Focal segmental glomerulosclerosis (FSGS) is a major cause of end-stage renal disease. Recent studies have proposed that plasma soluble urokinase receptor (suPAR) might be a causative circulating factor but this proposal has caused controversy. This study aimed to measure urinary suPAR levels in patients with primary FSGS and its significance in the pathogenesis of FSGS.
Sixty-two patients with primary FSGS, diagnosed between January 2006 and January 2012, with complete clinical and pathologic data were enrolled, together with disease and normal controls. Urinary suPAR levels were measured using commercial ELISA kits and were corrected by urinary creatinine (Cr). The associations between urinary suPAR levels and clinical data at presentation and during follow up were analyzed. Conditionally immortalized human podocytes were used to study the effect of urinary suPAR on activating β3 integrin detected by AP5 staining.
The urinary suPAR level of patients with primary FSGS (500.56, IQR 262.78 to 1,059.44 pg/μmol Cr) was significantly higher than that of patients with minimal change disease (307.86, IQR 216.54 to 480.18 pg/μmol Cr, P = 0.033), membranous nephropathy (250.23, IQR 170.37 to 357.59 pg/μmol Cr, P <0.001), secondary FSGS (220.45, IQR 149.38 to 335.54 pg/μmol Cr, P <0.001) and normal subjects (183.59, IQR 103.92 to 228.78 pg/μmol Cr, P <0.001). The urinary suPAR level of patients with cellular variant was significantly higher than that of patients with tip variant. The urinary suPAR level in the patients with primary FSGS was positively correlated with 24-hour urine protein (r = 0.287, P = 0.024). During follow up, the urinary suPAR level of patients with complete remission decreased significantly (661.19, IQR 224.32 to 1,115.29 pg/μmol Cr versus 217.68, IQR 121.77 to 415.55 pg/μmol Cr, P = 0.017). The AP5 signal was strongly induced along the cell membrane when human differentiated podocytes were incubated with the urine of patients with FSGS at presentation, and the signal could be reduced by a blocking antibody specific to uPAR.
Urinary suPAR was specifically elevated in patients with primary FSGS and was associated with disease severity. The elevated urinary suPAR could activate β3 integrin on human podocytes.
局灶节段性肾小球硬化(FSGS)是终末期肾病的主要病因。最近的研究提出,血浆可溶性尿激酶受体(suPAR)可能是一种致病循环因子,但这一观点引发了争议。本研究旨在测定原发性FSGS患者的尿suPAR水平及其在FSGS发病机制中的意义。
纳入2006年1月至2012年1月期间诊断的62例原发性FSGS患者,这些患者具有完整的临床和病理资料,同时纳入疾病对照组和正常对照组。使用商用ELISA试剂盒测定尿suPAR水平,并通过尿肌酐(Cr)进行校正。分析尿suPAR水平与就诊时及随访期间临床资料之间的关联。使用条件永生化人足细胞研究尿suPAR对通过AP5染色检测的β3整合素激活的影响。
原发性FSGS患者的尿suPAR水平(500.56,四分位间距262.78至1059.44 pg/μmol Cr)显著高于微小病变病患者(307.86,四分位间距216.54至480.18 pg/μmol Cr,P = 0.033)、膜性肾病患者(250.23,四分位间距170.37至357.59 pg/μmol Cr,P <0.001)、继发性FSGS患者(220.45,四分位间距149.38至335.54 pg/μmol Cr,P <0.001)和正常受试者(183.59,四分位间距103.92至228.78 pg/μmol Cr,P <0.001)。细胞型患者的尿suPAR水平显著高于顶端型患者。原发性FSGS患者的尿suPAR水平与24小时尿蛋白呈正相关(r = 0.287,P = 0.024)。随访期间,完全缓解患者的尿suPAR水平显著下降(661.19,四分位间距224.32至1115.29 pg/μmol Cr对比217.68,四分位间距121.77至415.55 pg/μmol Cr,P = 0.017)。当人分化足细胞与FSGS患者就诊时的尿液一起孵育时,AP5信号沿细胞膜强烈诱导,并且该信号可被uPAR特异性阻断抗体降低。
原发性FSGS患者的尿suPAR特异性升高,且与疾病严重程度相关。升高的尿suPAR可激活人足细胞上的β3整合素。