Hypoxia-inducible factor modulates tubular cell survival in cisplatin nephrotoxicity
Hypoxia-inducible factor modulates tubular cell survival in cisplatin nephrotoxicity
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DOI：
10.1152/ajprenal.00081.2005
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发表时间：
2005-11-01
影响因子：
4.2
通讯作者：
Nangaku, M
中科院分区：
文献类型：
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作者：
Tanaka, T;Kojima, I;Nangaku, M
缺氧诱导因子（Hypoxia-inducible factor，HIF）-1是一种介导细胞缺氧反应的转录因子。虽然它在缺血性肾脏的肾小管细胞中表达，但其功能作用在病理学背景下尚未完全阐明。在这项研究中，我们研究了HIF在顺铂诱导的肾小管细胞凋亡中的作用。顺铂（6 mg/kg）给药后3天，HIF-1 α在外髓质的肾小管细胞中表达。与溶剂组相比，体内给予钴激活缺氧诱导因子后，外髓中凋亡的肾小管细胞数量变得少得多。我们还研究了HIF-1在体外使用永生化大鼠近端肾小管细胞（IRPTC）的功能作用。在低氧条件下，表达显性负性（dn）HIF-1 α的IRPTC在不同剂量（25-100 μ M，24 h）的顺铂损伤中表现出受损的存活率，这在常氧条件下并不明显。观察到的缺氧中细胞活力的差异与dnHIF-1 α克隆中凋亡细胞数量的增加有关（Hoechst 33258染色）。对细胞内信号传导的研究表明，细胞色素c释放的程度、线粒体膜电位的消散和半胱天冬酶-9活性在dnHIF-1 α克隆中比在对照IRPTC中都更突出，这表明线粒体途径的信号传导加速。我们认为HIF- 1通过稳定线粒体膜的完整性和抑制凋亡信号转导减少凋亡细胞的数量，介导缺氧肾小管细胞对顺铂损伤的细胞保护作用。提示HIF- 1的激活可能成为治疗缺氧性肾脏疾病的新靶点。
Hypoxia-inducible factor (HIF)-1 is a transcription factor mediating cellular response to hypoxia. Although it is expressed in tubular cells of the ischemic kidney, its functional role is not fully clarified in the pathological context. In this study, we investigated a role of HIF in tubular cell apoptosis induced by cisplatin. HIF-1 alpha was expressed in tubular cells in the outer medulla 3 days after cisplatin (6 mg/kg) administration. With the in vivo administration of cobalt to activate HIF, the number of apoptotic renal tubular cells became much smaller in the outer medulla, compared with the vehicle group. We also examined the functional role of HIF-1 in vitro using immortalized rat proximal tubular cells (IRPTC). In hypoxia, IRPTC that express dominant-negative (dn) HIF-1 alpha showed impaired survival in cisplatin injury at variable doses (25-100 mu M, 24 h), which was not obvious in normoxia. The observed difference in cell viability in hypoxia was associated with the increased number of apoptotic cells in dnHIF-1 alpha clones ( Hoechst 33258 staining). Studies on intracellular signaling revealed that the degree of cytochrome c release, dissipation of mitochondrial membrane potentials, and caspase-9 activity were all more prominent in dnHIF-1 alpha clones than in control IRPTC, pointing to the accelerated signaling of mitochondrial pathways. We propose that HIF- 1 mediates cytoprotection against cisplatin injury in hypoxic renal tubular cells, by reducing the number of apoptotic cells through stabilization of mitochondrial membrane integrity and suppression of apoptosis signaling. A possibility was suggested that activation of HIF- 1 could be a new promising therapeutic target for hypoxic renal diseases.