Transcriptome analysis of human diabetic kidney disease.
Transcriptome analysis of human diabetic kidney disease.
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作者：
Woroniecka KI;Park AS;Mohtat D;Thomas DB;Pullman JM;Susztak K
在美国，糖尿病肾病（DKD）是导致肾衰竭的唯一主要原因，目前尚未找到治疗方法。我们研究的目的是为人类糖尿病肾活检样本的基因表达变化提供一个公正的目录。Affymetrix表达阵列用于鉴定44个微解剖人体肾脏样本中的差异调控转录本。DKD样品具有显著的种族多样性和肾小球滤过率降低（~ 25-35 mL/min）。采用Benjamini-Hochberg校正双尾t检验进行严格的统计分析，以识别对照组和患病肾小球和小管中的差异表达转录物。使用两种不同的基于网络的算法来定义差异调节的通路。我们在DKD肾小球中发现了1700个差异表达的基因，在糖尿病小管中发现了1831个差异表达的基因，其中330个基因在两个小室中都存在普遍差异表达。通路分析强调了Ras同源基因家族成员A、Cdc42、整合素、整合素连接激酶和血管内皮生长因子信号在DKD肾小球中的调控作用。小管间质室显示炎症相关通路的强烈富集。典型补体信号通路在DKD肾小球和小管中均有统计学差异调节，即使在不同的DKD样本中也与肾小球硬化的增加有关。我们的研究已经对基因表达调控进行了编目，并确定了可能在DKD发病机制中发挥作用或可作为生物标志物的多个新基因和途径。
Diabetic kidney disease (DKD) is the single leading cause of kidney failure in the U.S., for which a cure has not yet been found. The aim of our study was to provide an unbiased catalog of gene-expression changes in human diabetic kidney biopsy samples. Affymetrix expression arrays were used to identify differentially regulated transcripts in 44 microdissected human kidney samples. DKD samples were significant for their racial diversity and decreased glomerular filtration rate (~25–35 mL/min). Stringent statistical analysis, using the Benjamini-Hochberg corrected two-tailed t test, was used to identify differentially expressed transcripts in control and diseased glomeruli and tubuli. Two different web-based algorithms were used to define differentially regulated pathways. We identified 1,700 differentially expressed probesets in DKD glomeruli and 1,831 in diabetic tubuli, and 330 probesets were commonly differentially expressed in both compartments. Pathway analysis highlighted the regulation of Ras homolog gene family member A, Cdc42, integrin, integrin-linked kinase, and vascular endothelial growth factor signaling in DKD glomeruli. The tubulointerstitial compartment showed strong enrichment for inflammation-related pathways. The canonical complement signaling pathway was determined to be statistically differentially regulated in both DKD glomeruli and tubuli and was associated with increased glomerulosclerosis even in a different set of DKD samples. Our studies have cataloged gene-expression regulation and identified multiple novel genes and pathways that may play a role in the pathogenesis of DKD or could serve as biomarkers.