Human Nephrosclerosis Triggers a Hypoxia-Related Glomerulopathy
Human Nephrosclerosis Triggers a Hypoxia-Related Glomerulopathy
复制标题
DOI：
10.2353/ajpath.2010.090268
复制
发表时间：
2010-02-01
影响因子：
6
通讯作者：
Cohen, Clemens D.
中科院分区：
文献类型：
--
作者：
Neusser, Matthias A.;Lindenmeyer, Maja T.;Cohen, Clemens D.
肾脏缺氧。导致肾小管间质纤维化，但其对肾小球损伤和肾小球硬化的影响知之甚少。慢性缺氧被认为与肾硬化（NSC）或“高血压性肾病”有关。“在本研究中，研究了来自显微切割肾小球的全基因组表达数据，以检查缺氧在人类NSC肾小球硬化中的作用。功能注释分析揭示了NSC中缺氧相关生物过程的显着调节，包括血管生成、纤维化和炎症。在NSC中，由缺氧诱导因子（HIF）调节的大多数基因的肾小球表达水平显著改变。在这些HIF靶点中，趋化因子C-X-C基序受体4（CXCR 4）被显著诱导。通过定量RT-PCR证实了NSC独立队列中肾小球CXCR 4 mRNA的诱导，但未在其他肾小球疾病中。免疫组化结果显示，CXCR 4在神经干细胞的足细胞中表达增强。这种CXCR 4阳性仅与NSC足细胞中HIF 1 α的核定位相关，表明HIF的转录活性。由于CXCR 4配体CXCL 12/SDF-1在足细胞中组成性表达，自分泌信号可能有助于NSC。此外，在体外划痕试验中，阻断CXCR 4抗体引起足细胞对伤口闭合的显著抑制。这些数据支持CXCR 4/CXCL 12在人NSC中的作用，并表明缺氧不仅参与肾小管间质纤维化，而且有助于NSC中的肾小球损伤。(Am J Pathol 2010，176：594-607; DOI：10.2353/ajpath.2010.090268）
In die kidney, hypoxia. contributes to tubulointerstitial fibrosis, but little is known about its implications for glomerular damage and glomerulosclerosis. Chronic hypoxia was hypothesized to be involved in nephrosclerosis (NSC) or "hypertensive nephropathy." in the present study genome-wide expression data from microdissected glomeruli were studied to examine the role of hypoxia in glomerulosclerosis of human NSC. Functional annotation analysis revealed prominent regulation of hypoxia-associated biological processes in NSC, including angiogenesis, fibrosis, and inflammation. Glomerular expression levels of a majority of genes regulated by the hypoxia inducible factors (HIFs) were significantly altered in NSC. Among these HIF targets, chemokine C-X-C motif receptor 4 (CXCR4) was prominently induced. Glomerular CXCR4 mRNA induction was confirmed by quantitative RT-PCR in an independent cohort with NSC but not in those with other glomerulopathies. By inummohistological analysis, CXCR4 showed enhanced positivity in podocytes in NSC biopsy specimens. This CXCR4 positivity was associated with nuclear localization of HIF1 alpha only in podocytes of NSC, indicating transcriptional activity of HIF. As the CXCR4 ligand CXCL12/SDF-1 is constitutively expressed in podocytes, autocrine signaling may contribute to NSC. in addition, a blocking CXCR4 antibody caused significant inhibition of wound closure by podocytes in an in vitro scratch assay. These data support a role for CXCR4/CXCL12 in human NSC and indicate that hypoxia not only is involved in tubulointerstitial fibrosis but also contributes to glomerular damage in NSC. (Am J Pathol 2010, 176:594-607; DOI: 10.2353/ajpath.2010.090268)