1. HIF-1α is transcriptionally regulated by NF-κB in acute kidney injury
- Author
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Bi-Cheng Liu, Di Yin, Song-Tao Feng, Yi Wen, Bin Wang, Wei-jie Ni, Zuo-Lin Li, Lin-Li Lv, Naresh Kharbuja, Jia-Ling Ji, Jing-Yuan Cao, and Hong Liu
- Subjects
Physiology ,Inflammation ,Kidney ,urologic and male genital diseases ,Pathogenesis ,Mice ,chemistry.chemical_compound ,Nitriles ,Oxygen homeostasis ,medicine ,Transcriptional regulation ,Animals ,Sulfones ,Transcription factor ,Cells, Cultured ,urogenital system ,business.industry ,NF-kappa B ,Acute kidney injury ,Epithelial Cells ,NF-κB ,Acute Kidney Injury ,Hypoxia-Inducible Factor 1, alpha Subunit ,medicine.disease ,female genital diseases and pregnancy complications ,Editorial ,medicine.anatomical_structure ,Gene Expression Regulation ,chemistry ,Cancer research ,medicine.symptom ,business - Abstract
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.
- Published
- 2021