HIF-1α is transcriptionally regulated by NF-κB in acute kidney injury.

Zuo-Lin Li, Jia-Ling Ji, Yi Wen, Jing-Yuan Cao, Naresh Kharbuja, Wei-Jie Ni, Di Yin, Song-Tao Feng, Hong Liu, Lin-Li Lv, Bi-Cheng Liu, Bin Wang

American journal of physiology. Renal physiology 2021 Aug 01

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Oxygen homeostasis disturbances play a critical role in the pathogenesis of acute kidney injury (AKI). The transcription factor hypoxia-inducible factor-1 (HIF-1) is a master regulator of adaptive responses to hypoxia. Aside from posttranslational hydroxylation, the mechanism of HIF-1 regulation in AKI remains largely unclear. In this study, the mechanism of HIF-α regulation in AKI was investigated. We found that tubular HIF-1α expression significantly increased at the transcriptional level in ischemia-reperfusion-, unilateral ureteral obstruction-, and sepsis-induced AKI models, which was closely associated with macrophage-dependent inflammation. Meanwhile, NF-κB, which plays a central role in the inflammation response, was involved in the increasing expression of HIF-1α in AKI, as evidenced by pharmacological modulation (NF-κB inhibitor BAY11-7082). Mechanistically, NF-κB directly bound to the HIF-1α promoter and enhanced its transcription, which occurred not only under hypoxic conditions but also under normoxic conditions. Moreover, the induced HIF-1α by inflammation protected against tubular injury in AKI. Thus, our findings not only provide novel insights into HIF-1 regulation in AKI but also offer to understand the pathophysiology of kidney diseases.NEW & NOTEWORTHY Here, the mechanism of hypoxia-inducible factor-α (HIF-α) regulation in acute kidney injury (AKI) was investigated. We found that tubular HIF-1α expression significantly increased at the transcriptional level, which was closely associated with macrophage-dependent inflammation. Meanwhile, NF-κB was involved in the increasing expression of HIF-1α in AKI. Mechanistically, NF-κB directly bound to the HIF-1α promoter and enhanced its transcription. Our findings not only provide novel insights into HIF-1 regulation in AKI but also offer to understand the pathophysiology of kidney diseases.

Citation

Zuo-Lin Li, Jia-Ling Ji, Yi Wen, Jing-Yuan Cao, Naresh Kharbuja, Wei-Jie Ni, Di Yin, Song-Tao Feng, Hong Liu, Lin-Li Lv, Bi-Cheng Liu, Bin Wang. HIF-1α is transcriptionally regulated by NF-κB in acute kidney injury. American journal of physiology. Renal physiology. 2021 Aug 01;321(2):F225-F235