Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
Kidney Int. 2010 Nov;78(9):857-67. doi: 10.1038/ki.2010.284. Epub 2010 Aug 18.
The two hypoxia-inducible factors (HIF-1α and HIF-2α) are transcription factors that regulate the response to hypoxia. Recently, the factor inhibiting HIF (FIH1) was identified as a molecular oxygen-dependent dioxygenase that blunts the transcriptional activity of HIF and has also been implicated in HIF-dependent and -independent hypoxia responses. Interestingly, HIF accumulation in the kidney has been shown to confer renal protection and to also cause glomerular injury or enhance renal fibrosis. In order to better understand the regulation of hypoxia-inducible genes, we determined the expression of FIH1 in the kidney and its functional role in isolated renal cells. FIH1 was expressed only in distal tubules and in podocytes, thus showing a very distinct expression pattern, partially overlapping with sites of HIF-1α expression. In tubular cells, RNA silencing of FIH1 caused transcriptional activation of HIF target genes during hypoxia. In contrast, FIH1 silencing in podocytes enhanced transcription of hypoxia-inducible genes in an HIF-independent manner. Using the anti-Thy.1 rat model of glomerulonephritis, we found a gradual decrease of glomerular FIH1 expression during disease progression paralleled by an increase in hypoxia-inducible genes including CXCR4, a mediator of glomerular inflammation. Thus, FIH1 appears to be a suppressor of oxygen-dependent genes in the kidney, operating through HIF-dependent and -independent mechanisms.
两种缺氧诱导因子（HIF-1α 和 HIF-2α）是调节缺氧反应的转录因子。最近，发现因子抑制 HIF（FIH1）是一种分子氧依赖性双氧酶，可减弱 HIF 的转录活性，并且还与 HIF 依赖性和非依赖性缺氧反应有关。有趣的是，研究表明肾脏中 HIF 的积累可提供肾脏保护作用，同时也会导致肾小球损伤或增强肾脏纤维化。为了更好地理解缺氧诱导基因的调节，我们确定了 FIH1 在肾脏中的表达及其在分离的肾细胞中的功能作用。FIH1 仅在远端肾小管和足细胞中表达，因此表现出非常独特的表达模式，部分与 HIF-1α 的表达部位重叠。在肾小管细胞中，FIH1 的 RNA 沉默在缺氧期间导致 HIF 靶基因的转录激活。相比之下，足细胞中 FIH1 的沉默以 HIF 非依赖性方式增强了缺氧诱导基因的转录。使用抗 Thy.1 大鼠肾小球肾炎模型，我们发现肾小球 FIH1 的表达在疾病进展过程中逐渐降低，同时缺氧诱导基因包括 CXCR4 的表达增加，CXCR4 是肾小球炎症的介质。因此，FIH1 似乎是肾脏中氧依赖性基因的抑制剂，通过 HIF 依赖性和非依赖性机制发挥作用。
