Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Am J Pathol. 2010 Oct;177(4):1674-86. doi: 10.2353/ajpath.2010.090746. Epub 2010 Sep 16.
Focal segmental glomerulosclerosis (FSGS) is a common form of idiopathic nephrotic syndrome defined by the characteristic lesions of focal glomerular sclerosis and foot process effacement; however, its etiology and pathogenesis are unknown. We used mRNA isolated from laser-captured glomeruli from archived formalin-fixed, paraffin-embedded renal biopsies, until recently considered an unsuitable source of mRNA for microarray analysis, to investigate the glomerular gene expression profiles of patients with primary classic FSGS, collapsing FSGS (COLL), minimal change disease (MCD), and normal controls (Normal). Amplified mRNA was hybridized to an Affymetrix Human X3P array. Unsupervised (unbiased) hierarchical clustering revealed two distinct clusters delineating FSGS and COLL from Normal and MCD. Class comparison analysis of FSGS + COLL combined versus Normal + MCD revealed 316 significantly differentially regulated genes (134 up-regulated, 182 down-regulated). Among the differentially regulated genes were those known to be part of the slit diaphragm junctional complex and those previously described in the dysregulated podocyte phenotype. Analysis based on Gene Ontology categories revealed overrepresented biological processes of development, differentiation and morphogenesis, cell motility and migration, cytoskeleton organization, and signal transduction. Transcription factors associated with developmental processes were heavily overrepresented, indicating the importance of reactivation of developmental programs in the pathogenesis of FSGS. Our findings reveal novel insights into the molecular pathogenesis of glomerular injury and structural degeneration in FSGS.
局灶节段性肾小球硬化症（FSGS）是特发性肾病综合征的一种常见形式，其特征病变为局灶性肾小球硬化和足细胞足突消失；然而，其病因和发病机制尚不清楚。我们使用从最近被认为不适合进行微阵列分析的存档福尔马林固定、石蜡包埋肾活检的激光捕获肾小球中分离的 mRNA ，来研究原发性经典 FSGS、塌陷性 FSGS（COLL）、微小病变性肾病（MCD）和正常对照（Normal）患者的肾小球基因表达谱。扩增的 mRNA 与 Affymetrix Human X3P 芯片杂交。无监督（无偏）层次聚类显示出两个不同的簇，将 FSGS 和 COLL 与 Normal 和 MCD 区分开来。对 FSGS+COLL 组合与 Normal+MCD 的分类比较分析显示，有 316 个显著差异调节基因（134 个上调，182 个下调）。在差异调节基因中，有一些是已知的裂隙隔膜连接复合体的一部分，还有一些是以前在失调的足细胞表型中描述过的。基于基因本体论类别的分析显示，发育、分化和形态发生、细胞运动和迁移、细胞骨架组织和信号转导等生物学过程过度表达。与发育过程相关的转录因子也大量过度表达，这表明在 FSGS 的发病机制中重新激活发育程序的重要性。我们的研究结果揭示了肾小球损伤和 FSGS 结构退化的分子发病机制的新见解。
