Active focal segmental glomerulosclerosis is associated with massive oxidation of plasma albumin
Active focal segmental glomerulosclerosis is associated with massive oxidation of plasma albumin
复制标题
DOI：
10.1681/asn.2006090965
复制
发表时间：
2007-03-01
影响因子：
13.6
通讯作者：
Ghiggeri, Gian Marco
中科院分区：
文献类型：
--
作者：
Musante, Luca;Candiano, Giovanni;Ghiggeri, Gian Marco
特发性FSGS的基本机制仍不清楚。在人类中的间接证据和实验模型中氧化剂产生的FSGS表明自由基的作用。体外研究表明，血浆白蛋白作为抗氧化剂的主要作用，其修饰代表氧化应激的化学标志物。使用互补液相色谱电喷雾串联质谱（LC-ESI-MS/MS）和生化方法，血浆白蛋白的特点是在34例FSGS患者，18人接受了肾移植，17 IgM系膜沉积。移植后缓解或未复发的FSGS患者血浆白蛋白正常，原发性和继发性肾炎以及慢性肾功能衰竭患者也是如此。相反，活动性FSGS或移植后复发的患者有氧化血浆白蛋白。这一发现是基于白蛋白Cys 34的表征，其三重电荷的质荷比为511.71，这与形成携带磺酸基的磺基丙氨酸（alb-SO3-）一致。对于三个氧自由基的掺入，白蛋白的精确质量相应增加（+48 Da）。血浆白蛋白游离巯基34的直接滴定和电泳滴定曲线证实了所有疾病活动性病例中游离巯基的丢失和快速移动亚型的形成。这是第一次证明体内血浆白蛋白氧化，获得了充分的结构方法。白蛋白氧化似乎是特定的FSGS，提示一些发病机制的影响。FSGS中的自由基参与可能导致特定的治疗干预。
The basic mechanism for idiopathic FSGS still is obscure. Indirect evidence in humans and generation of FSGS by oxidants in experimental models suggest a role of free radicals. In vitro studies demonstrate a main role of plasma albumin as antioxidant, its modification representing a chemical marker of oxidative stress. With the use of complementary liquid chromatography electron spray ionization tandem mass spectrometry (LC-ESI-MS/MS) and biochemical methods, plasma albumin was characterized in 34 patients with FSGS; 18 had received a renal transplant, and 17 had IgM mesangial deposition. Patients with FSGS that was in remission or without recurrence after transplantation had normal plasma albumin, and the same occurred in patients with primary and secondary nephrites and with chronic renal failure. In contrast, patients with active FSGS or with posttransplantation recurrence had oxidized plasma albumin. This finding was based on the characterization of albumin Cys 34 with an mass-to-charge ratio of 511.71 in triple charge that was consistent with the formation of a cysteic acid carrying a sulfonic group (alb-SO3-). The exact mass of albumin was increased accordingly (+48 Da) for incorporation of three oxygen radicals. Direct titration of the free sulfhydryl group 34 of plasma albumin and electrophoretic titration curves confirmed loss of free sulfhydryl group and formation of a fast-moving isoform in all cases with disease activity. This is the first demonstration of in vivo plasma albumin oxidation that was obtained with an adequate structural approach. Albumin oxidation seems to be specific for FSGS, suggesting some pathogenetic implications. Free radical involvement in FSGS may lead to specific therapeutic interventions.