Interstitial vascular rarefaction and reduced VEGF-A expression in human diabetic nephropathy
Interstitial vascular rarefaction and reduced VEGF-A expression in human diabetic nephropathy
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DOI：
10.1681/asn.2006121304
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发表时间：
2007-06-01
影响因子：
13.6
通讯作者：
Cohen, Clemens D.
中科院分区：
文献类型：
--
作者：
Lindenmeyer, Maja T.;Kretzler, Matthias;Cohen, Clemens D.
糖尿病肾病（DN）是糖尿病患者常见的并发症。尽管大多数 DN 模型和人体研究都集中在肾小球，但肾小管间质损伤是 DN 的主要特征，也是肾功能障碍的重要预测因子。本研究旨在探讨 DN 患者肾间质致病途径的分子标记。对来自已确定 DN 的活检组织和对照肾脏的显微解剖的肾小管间质区室进行表达谱分析。根据常见假设，对可能与 DN 相关的候选基因进行分析，确定了 49 个基因，与对照相比，在已建立的 DN 中表达水平显着改变。与一些啮齿动物模型相比，DN 中生长因子血管内皮生长因子 A (VEGF-A) 和表皮生长因子 (EGF) 的 mRNA 表达降低。通过实时逆转录酶 PCR 在独立的 DN 患者队列中验证了这一点。 VEGF-A 和 EGF 的免疫组织化学染色也显示 DN 中的表达降低。肾 VEGF-A 表达的减少与血小板内皮细胞粘附分子 1/CD31 染色显示的肾小管周围毛细血管密度的减少有关。此外，发现VEGF-A与蛋白尿以及EGF与蛋白尿之间呈显着负相关，而VEGF-A与缺氧诱导因子-1a mRNA之间呈正相关。因此，在人类 DN 中，VEGF-A 的减少，而不是某些啮齿动物模型中所报道的增加，可能会导致疾病进展。这些发现和问题
Diabetic nephropathy (DN) is a frequent complication in patients with diabetes. Although the majority of DN models and human studies have focused on glomeruli, tubulointerstitial damage is a major feature of DN and an important predictor of renal dysfunction. This study sought to investigate molecular markers of pathogenic pathways in the renal interstitium of patients with DN. Microdissected tubulointerstitial compartments from biopsies with established DN and control kidneys were subjected to expression profiling. Analysis of candidate genes, potentially involved in DN on the basis of common hypotheses, identified 49 genes with significantly altered expression levels in established DN in comparison with controls. In contrast to some rodent models, the growth factors vascular endothelial growth factor A (VEGF-A) and epidermal growth factor (EGF) showed a decrease in mRNA expression in DN. This was validated on an independent cohort of patients with DN by real-time reverse transcriptase-PCR. Immunohistochemical staining for VEGF-A and EGF also showed a reduced expression in DN. The decrease of renal VEGF-A expression was associated with a reduction in peritubular capillary densities shown by platelet-endothelial cell adhesion molecule-1/CD31 staining. Furthermore, a significant inverse correlation between VEGF-A and proteinuria, as well as EGF and proteinuria, and a positive correlation between VEGF-A and hypoxia-inducible factor-la mRNA was found. Thus, in human DN, a decrease of VEGF-A, rather than the reported increase as described in some rodent models, may contribute to the progressive disease. These findings and the questions