a role of HIF-3 in adjusting cellular hypoxia response and its implications in progressive renal disease

HIF-3 在调节细胞缺氧反应中的作用及其对进行性肾病的影响

• 批准号: 22790781
• 负责人: TANAKA TETSUHIRO
• 金额: $ 2.41万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22790781/
• 关键词: HIF-3; 進行性腎疾患; 慢性腎臓病; 低酸素; HIF

In this study, we investigated a role of hypoxia-inducible factor (HIF)-3 as a regulator of cellular hypoxia response by HIF-1. HIF-3alpha mRNA was transcriptionally up-regulated by hypoxia in a HIF-1- dependent manner. Promoter analysis revealed that HIF-3alpha is a novel HIF-1 target gene. Overexpression of HIF-3alpha in a human proximal tubular cell line, HK-2, reduced the hypoxic induction of lysyl-oxidase most significantly among other known HIF targets. Functionally, HIF-3 counteracted the disappearance of epithelial markers, such as E-cadherin, by hypoxia and inhibited the acquisition of cell migration. In immunohistochemistry, the expression of HIF-3alpha was most evident in the nuclei of tubular epithelial cells in various models of CKD representing fibrosis. In summary, results of the present study clarify the importance of HIF-3 in counteracting kidney fibrosis in the hypoxic environment.

在这项研究中，我们研究了缺氧诱导因子（HIF）-3作为HIF-1的细胞缺氧反应的调节剂的作用。缺氧可使HIF-3 α mRNA表达上调，且呈HIF-1依赖性。启动子分析表明HIF-3 α是一个新的HIF-1靶基因。HIF-3 α在人近端肾小管细胞系HK-2中的过表达在其他已知的HIF靶点中最显著地降低了赖氨酰氧化酶的缺氧诱导。在功能上，HIF-3抵消了上皮标志物的消失，如E-钙粘蛋白，缺氧和抑制细胞迁移的收购。在免疫组织化学中，HIF-3 α的表达在代表纤维化的各种CKD模型中的肾小管上皮细胞的细胞核中最明显。总之，本研究的结果阐明了HIF-3在缺氧环境中对抗肾纤维化的重要性。

项目成果

Indoxyl Sulfate Induces Cbp/p300-Interacting Transactivator, with Glu/Asp-Rich Carboxy-Terminal Domain, 2, and Impairs Hypoxia Response in Proximal Tubular Cells

硫酸吲哚酚诱导 Cbp/p300 相互作用反式激活因子（具有富含 Glu/Asp 的羧基末端结构域 2），并损害近端肾小管细胞的缺氧反应

• 发表时间: 2011
• 作者: Tanaka T;Fujita T;Nangaku M
• 通讯作者: Nangaku M

HYPOXIA-INDUCIBLE FACTOR (HIF) 3 IS UPREGULATED BY HYPOXIA AND COUNTERACTS THE EPITHELIAL-MESENCHYMAL TRANSDIFFERENTIATION PROGRAM

缺氧诱导因子 (HIF) 3 因缺氧而上调并抵消上皮-间质转分化程序

• 发表时间: 2013
• 作者: Tetsuhiro Tanaka;Kumi Shoji;Junna Yamaguchi;Masaomi Nangaku
• 通讯作者: Masaomi Nangaku

Indoxyl sulfate induces Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 2 (CITED2), via the mitogen-activated protein kinase cascade and impairs hypoxia response of tubular epithelial cells

硫酸吲哚酚通过丝裂原激活的蛋白激酶级联诱导具有富含 Glu/Asp 的羧基末端结构域 2 (CITED2) 的 Cbp/p300 相互作用反式激活因子，并损害肾小管上皮细胞的缺氧反应

• 发表时间: 2012
• 作者: Tetsuhiro Tanaka;Junna Yamaguchi;Masaomi Nangaku
• 通讯作者: Masaomi Nangaku

尿毒素インドキシル硫酸は近位尿細管の酸素消費を亢進させ,慢性低酸素をもたらす

尿毒症毒素硫酸吲哚酚增加近曲小管的耗氧量，导致慢性缺氧

• 发表时间: 2010
• 作者: 田中哲洋;南学正臣;川上貴久;西島冬彦;坂内堅二;Fredrik Palm;藤田敏郎
• 通讯作者: 藤田敏郎

The role of incretins in salt-sensitive hypertension : the potential use of dipeptidyl peptidase-IV inhibitors

肠降血糖素在盐敏感性高血压中的作用：二肽基肽酶-IV 抑制剂的潜在用途

• 发表时间: 2011
• 期刊: Curr Opin Nephrol Hypertens
• 作者: Tanaka T;Nangaku M;Nishiyama A
• 通讯作者: Nishiyama A