Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition
Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition
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DOI：
10.1172/jci30487
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发表时间：
2007-12-01
影响因子：
15.9
通讯作者：
Haase, Volker H.
中科院分区：
文献类型：
--
作者：
Higgins, Debra F.;Kimura, Kuniko;Haase, Volker H.
低氧已被认为是组织纤维化发展中的一个重要微环境因素，然而，其潜在机制尚未明确。为了研究缺氧诱导因子-1（HIF-1）（细胞适应缺氧的关键介质）在小鼠纤维化发展中的作用，我们使用Cre-loxP介导的基因靶向技术灭活了单侧输尿管梗阻（UUO）肾原代上皮细胞和近端小管中的HIF-1 α。我们发现HIF-1 α在体外增强了上皮细胞向间充质细胞转化（EMT），并通过上调赖氨酰氧化酶基因诱导上皮细胞迁移。上皮Hif-1 α的基因消融抑制了UUO肾脏中肾小管间质纤维化的发展，这与间质胶原沉积减少、炎性细胞浸润减少和成纤维细胞特异性蛋白-1表达（FSP-1表达）间质细胞数量减少有关。此外，我们还证实慢性肾脏疾病患者肾脏HIF-1 α表达增加与肾小管间质损伤相关。因此，我们提供的临床和遗传学证据表明，肾上皮细胞中HIF-1信号的激活与慢性肾脏疾病的发展有关，并可能通过增加细胞外基质修饰因子和赖氨酰氧化酶基因的表达以及促进EMT来促进纤维化。
Hypoxia has been proposed as an important microenvironmental factor in the development of tissue fibrosis; however, the underlying mechanisms are not well defined. To examine the role of hypoxia-inducible factor-1 (HIF-1), a key mediator of cellular adaptation to hypoxia, in the development of fibrosis in mice, we inactivated Hif-1 alpha in primary renal epithelial cells and in proximal tubules of kidneys subjected to unilateral ureteral obstruction (UUO) using Cre-loxP-mediated gene targeting. We found that Hif-1 alpha enhanced epithelial-tomesenchymal transition (EMT) in vitro and induced epithelial cell migration through upregulation of lysyl oxidase genes. Genetic ablation of epithelial Hif-1 alpha inhibited the development of tubulointerstitial fibrosis in UUO kidneys, which was associated with decreased interstitial collagen deposition, decreased inflammatory cell infiltration, and a reduction in the number of fibroblast-specific protein-1-expressing (FSP-1-expressing) interstitial cells. Furthermore, we demonstrate that increased renal HIF-1 alpha expression is associated with tubulointerstitial injury in patients with chronic kidney disease. Thus, we provide clinical and genetic evidence that activation of HIF-1 signaling in renal epithelial cells is associated with the development of chronic renal disease and may promote fibrogenesis by increasing expression of extracellular matrix-modifying factors and lysyl oxidase genes and by facilitating EMT.