FIH-1-modulated HIF-1α C-TAD promotes acute kidney injury to chronic kidney disease progression via regulating KLF5 signaling
FIH-1-modulated HIF-1α C-TAD promotes acute kidney injury to chronic kidney disease progression via regulating KLF5 signaling
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DOI：
10.1038/s41401-021-00617-4
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发表时间：
2021-03-03
影响因子：
8.2
通讯作者：
Liu, Bi-cheng
中科院分区：
文献类型：
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作者：
Li, Zuo-lin;Wang, Bin;Liu, Bi-cheng
急性肾损伤（AKI）发作后的不完全恢复可使患者易患慢性肾病（CKD）。虽然缺氧诱导因子-1 α (HIF-1 α)是缺氧/缺血反应的主要调节因子，但HIF-1 α在AKI不完全恢复后CKD进展中的作用尚不清楚。在这里，我们使用中度和重度缺血/再灌注损伤（I/RI）小鼠模型来研究这个问题。我们发现AKI的预后与管状HIF-1 α表达的时间过程高度相关。HIF-1 α的持续激活，伴随着肾纤维化病变的发展，在严重AKI的肾脏中被发现。从严重I/RI后第5天开始连续10天给予PX-478（一种特异性HIF-1 α抑制剂，5mg中心dot kg（-1）中心dot d(-1), i.p）， AKI向CKD进展明显改善。此外，我们证明HIF-1 α c末端转录激活域（C-TAD）转录刺激KLF5，从而促进重度AKI后CKD的进展。体内和体外研究也证实了HIF-1 α C-TAD激活促进AKI向CKD进展的作用。此外，我们发现HIF-1 α C-TAD的激活导致FIH-1的缺失，而FIH-1是控制HIF-1 α驱动的AKI到CKD进展的关键因素。过表达FIH-1抑制HIF-1 α - C-TAD，阻止AKI向CKD进展。因此，通过转录调节KLF5通路，fih -1调节HIF-1 α C-TAD激活是AKI向CKD进展的关键机制。我们的研究结果为HIF-1 α在AKI和CKD进展中的作用以及预防肾脏疾病进展的潜在治疗策略提供了新的见解。
Incomplete recovery from episodes of acute kidney injury (AKI) can predispose patients to develop chronic kidney disease (CKD). Although hypoxia-inducible factor-1 alpha (HIF-1 alpha) is a master regulator of the response to hypoxia/ischemia, the role of HIF-1 alpha in CKD progression following incomplete recovery from AKI is poorly understood. Here, we investigated this issue using moderate and severe ischemia/reperfusion injury (I/RI) mouse models. We found that the outcomes of AKI were highly associated with the time course of tubular HIF-1 alpha expression. Sustained activation of HIF-1 alpha, accompanied by the development of renal fibrotic lesions, was found in kidneys with severe AKI. The AKI to CKD progression was markedly ameliorated when PX-478 (a specific HIF-1 alpha inhibitor, 5 mg center dot kg(-1)center dot d(-1), i.p.) was administered starting on day 5 after severe I/RI for 10 consecutive days. Furthermore, we demonstrated that HIF-1 alpha C-terminal transcriptional activation domain (C-TAD) transcriptionally stimulated KLF5, which promoted progression of CKD following severe AKI. The effect of HIF-1 alpha C-TAD activation on promoting AKI to CKD progression was also confirmed in in vivo and in vitro studies. Moreover, we revealed that activation of HIF-1 alpha C-TAD resulted in the loss of FIH-1, which was the key factor governing HIF-1 alpha-driven AKI to CKD progression. Overexpression of FIH-1 inhibited HIF-1 alpha C-TAD and prevented AKI to CKD progression. Thus, FIH-1-modulated HIF-1 alpha C-TAD activation was the key mechanism of AKI to CKD progression by transcriptionally regulating KLF5 pathway. Our results provide new insights into the role of HIF-1 alpha in AKI to CKD progression and also the potential therapeutic strategy for the prevention of renal diseases progression.