Proteomic patterns and prediction of glomerulosclerosis and its mechanisms
Proteomic patterns and prediction of glomerulosclerosis and its mechanisms
复制标题
DOI：
10.1681/asn.2005030262
复制
发表时间：
2005-10-01
影响因子：
13.6
通讯作者：
Fogo, AB
中科院分区：
文献类型：
--
作者：
Xu, BJ;Shyr, Y;Fogo, AB
研究了局灶节段性肾小球硬化 5/6 肾切除 (Nx) 大鼠模型中与硬化相关的蛋白质表达谱。通过激光捕获显微切割分离来自正常基线 Nx 组织的对照肾小球切片以及来自 5/6 Nx 后 12 周的非硬化和硬化肾小球切片。通过基质辅助激光解吸/电离飞行时间质谱法直接获得蛋白质谱。区分正常肾小球与硬化肾小球的分类准确度为 99.2%，区分非硬化肾小球与正常肾小球和硬化肾小球的分类准确度分别为 96.7% 和 97.8%。非硬化性肾小球的蛋白质组模式比正常肾小球更类似于硬化性肾小球（P < 0.0001）。胸腺素β4是一种与纤溶酶原激活剂抑制剂1、血管生成和伤口愈合具有相关相互作用的蛋白质，被确定为关键的差异表达蛋白质。硬化肾小球（主要是内皮细胞）中胸腺素β4免疫染色增加。在培养的肾小球内皮细胞中，通过 RNAi 下调胸腺肽 β4 会降低血管紧张素 II 诱导的纤溶酶原激活剂抑制剂 1 的表达。总之，蛋白质组模式可以准确区分正常肾小球、非硬化肾小球和硬化肾小球。非硬化和硬化肾小球密切相关的蛋白质组模式表明，即使在看似完整的肾小球中，硬化机制也会早期激活。胸腺素β4是此类早期事件的标志物，甚至可能导致硬化。
Protein expression profiles linked to sclerosis in the 5/6 nephrectomy (Nx) rat model of focal segmental glomerulosclerosis were investigated. Sections of control glomeruli from normal baseline Nx tissue and nonsclerotic and sclerotic glomeruli from 12 wk after 5/6 Nx were isolated by laser capture microdissection. Protein profiles were acquired directly by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Classification accuracy was 99.2% for distinguishing normal versus sclerotic glomeruli and 96.7 and 97.8% for nonsclerotic versus normal and sclerotic glomeruli, respectively. The proteomic pattern of the nonsclerotic glomeruli was more similar to sclerotic than normal glomeruli (P < 0.0001). Thymosin beta 4, a protein with relevant interactions with plasminogen activator inhibitor-1, angiogenesis, and wound healing, was identified as a key differentially expressed protein. Thymosin beta 4 immunostaining was increased in sclerotic glomeruli, predominantly in endothelial cells. Downregulation of thymosin beta 4 by RNAi in cultured glomerular endothelial cells decreased angiotensin II-induced plasminogen activator inhibitor-1 expression. In conclusion, proteomic patterns can accurately distinguish normal versus nonsclerotic versus sclerotic glomeruli. The closely related proteomic patterns of nonsclerotic and sclerotic glomeruli suggest early activation of prosclerotic mechanisms even in seemingly intact glomeruli. Thymosin beta 4 is a marker of such early events and may even contribute to sclerosis.