Activation of HIF-1α C-terminal transactivation domain protects against hypoxia-induced kidney injury through hexokinase 2-mediated mitophagy.
Activation of HIF-1α C-terminal transactivation domain protects against hypoxia-induced kidney injury through hexokinase 2-mediated mitophagy.
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缺氧诱导因子-1α（HIF-1α）C端反式激活结构域的激活通过己糖激酶2介导的线粒体自噬，对缺氧诱导的肾损伤起到保护作用。
DOI：
10.1038/s41419-023-05854-5
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发表时间：
2023-05-24
影响因子：
9
通讯作者：
Liu, Bi-Cheng
中科院分区：
文献类型：
--
作者：
Li, Zuo-Lin;Ding, Lin;Ma, Rui-Xia;Zhang, Yue;Zhang, Yi-Lin;Ni, Wei-Jie;Tang, Tao-Tao;Wang, Gui-Hua;Wang, Bin;Lv, Lin-Li;Wu, Qiu-Li;Wen, Yi;Liu, Bi-Cheng
低氧诱导因子-1 α（hypoxia-inducible factor-1α，HIF-1α）是低氧适应性反应的主要调节因子，具有两个转录激活结构域[N-末端（N-terminal，N-terminal）和C-末端（C-terminal，C-terminal）]。虽然HIF-1α NF 3在肾脏疾病中的作用已被认识，但HIF-1α NF 3在肾脏疾病中的确切作用知之甚少。在这里，使用HIF-1α CXCR 4基因敲除（HIF-1 α CXCR 4 −/−）小鼠建立了两个独立的缺氧诱导的肾损伤小鼠模型。此外，己糖激酶2（HK 2）和线粒体自噬途径的调制，分别使用遗传和药理学方法。我们证明了HIF-1α C3 −/−在两种独立的缺氧诱导的肾损伤小鼠模型中加重了肾损伤，包括缺血/再灌注诱导的肾损伤和单侧输尿管梗阻诱导的肾病。从机制上讲，我们发现HIF-1α Cf 3可以转录调节HK 2，从而改善缺氧诱导的肾小管损伤。此外，发现HK 2缺乏通过线粒体自噬抑制导致严重的肾损伤，而使用尿石素A的线粒体自噬激活可以显着保护HIF-1α C-C −/−小鼠免受缺氧诱导的肾损伤。提示HIF-1α CTAD-HK 2通路是肾脏对缺氧反应的一种新机制，为缺氧性肾损伤的治疗提供了新的思路。
The transcription factor hypoxia-inducible factor-1α (HIF-1α), as a master regulator of adaptive responses to hypoxia, possesses two transcriptional activation domains [TAD, N-terminal (NTAD), and C-terminal (CTAD)]. Although the roles of HIF-1α NTAD in kidney diseases have been recognized, the exact effects of HIF-1α CTAD in kidney diseases are poorly understood. Here, two independent mouse models of hypoxia-induced kidney injury were established using HIF-1α CTAD knockout (HIF-1α CTAD−/−) mice. Furthermore, hexokinase 2 (HK2) and mitophagy pathway are modulated using genetic and pharmacological methods, respectively. We demonstrated that HIF-1α CTAD−/− aggravated kidney injury in two independent mouse models of hypoxia-induced kidney injury, including ischemia/reperfusion-induced kidney injury and unilateral ureteral obstruction-induced nephropathy. Mechanistically, we found that HIF-1α CTAD could transcriptionally regulate HK2 and subsequently ameliorate hypoxia-induced tubule injury. Furthermore, it was found that HK2 deficiency contributed to severe renal injury through mitophagy inhibition, while mitophagy activation using urolithin A could significantly protect against hypoxia-induced kidney injury in HIF-1α C-TAD−/− mice. Our findings suggested that the HIF-1α CTAD-HK2 pathway represents a novel mechanism of kidney response to hypoxia, which provides a promising therapeutic strategy for hypoxia-induced kidney injury.
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