Role of hypoxia-inducible factor-1 in the development of renal fibrosis in mouse obstructed kidney: Special references to HIF-1 dependent gene expression of profibrogenic molecules
Role of hypoxia-inducible factor-1 in the development of renal fibrosis in mouse obstructed kidney: Special references to HIF-1 dependent gene expression of profibrogenic molecules
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DOI：
10.1016/j.jphs.2017.12.004
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发表时间：
2018-01-01
影响因子：
3.5
通讯作者：
Miura, Katsuyuki
中科院分区：
文献类型：
--
作者：
Kabei, Kazuya;Tateishi, Yu;Miura, Katsuyuki
本研究的目的是阐明缺氧诱导因子-1（HIF-1）在小鼠梗阻性肾病肾纤维化发展中的作用。我们使用具有floxed HIF-1 α等位基因和在泛素C启动子下的他莫昔芬诱导的Cre/ERT 2重组酶的小鼠来诱导全局HIF-1 α缺失。在他莫昔芬给药后，使小鼠经受单侧输尿管梗阻（UUO）。在UUO后3、7和14天，评估肾脏基因表达谱和间质纤维化。缺氧诱导因子-1依赖的脯氨酰羟化酶3和葡萄糖转运蛋白-1的上调，观察到阻塞的肾脏在3和7天，但不是在14天后UUO。在纤维化的发展过程中，各种促进纤维化的因子表达上调。HIF-1依赖性基因表达的促纤维化分子，纤溶酶原激活物抑制剂1，结缔组织生长因子，赖氨酰氧化酶样2和转氨酶2中观察到阻塞的肾脏，但这种HIF-1依赖性仅限于早期发病的肾纤维化。全球HIF-1删除倾向于减弱间质胶原蛋白I沉积在3天，但此后没有影响。提示HIF-1依赖的促纤维化机制在肾纤维化的早期开始起作用，但其贡献随着小鼠UUO模型的进展而下降。(C)2018作者制作和主办由爱思唯尔B。V.代表日本药理学会。这是一个CC BY-NC-ND许可下的开放获取文章。
The aim of the study is to clarify the role of hypoxia-inducible factor-1 (HIF-1) in the development of renal fibrosis in mouse obstructive nephropathy. We used mice with floxed HIF-1 alpha alleles and tamoxifeninducible Cre/ERT2 recombinase under ubiquitin C promoter to induce global HIF-1 alpha deletion. Following tamoxifen administration, mice were subjected to unilateral ureteral obstruction (UUO). At 3, 7 and 14 days after UUO, renal gene expression profiles and interstitial fibrosis were assessed. HIF-1 dependent up-regulation of prolyl hydroxylase 3 and glucose transporter-1 was observed in the obstructed kidney at 3 and 7 days but not at 14 days after UUO. Various factors promoting fibrosis were up-regulated during the development of fibrosis. HIF-1 dependent gene expression of profibrotic molecules, plasminogen activator inhibitor 1, connective tissue growth factor, lysyl oxidase like 2 and transglutaminase 2 was observed in the obstructed kidney but such HIF-1 dependency was limited to the early onset of renal fibrosis. Global HIF-1 deletion tended to attenuate interstitial collagen I deposition at 3 days but had no effects thereafter. It is suggested that HIF-1 dependent profibrogenic mechanisms are operating at the early onset of renal fibrosis but its contribution declines with the progression in mouse UUO model. (C) 2018 The Authors. Production and hosting by Elsevier B. V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license.