Activation of HIF-1α C-terminal transactivation domain protects against hypoxia-induced kidney injury through hexokinase 2-mediated mitophagy

  • Cell Death Dis. 2023 May 24;14(5):339. doi: 10.1038/s41419-023-05854-5.
Zuo-Lin Li  1 ,  Lin Ding  2 ,  Rui-Xia Ma  3 ,  Yue Zhang  1 ,  Yi-Lin Zhang  1 ,  Wei-Jie Ni  1 ,  Tao-Tao Tang  1 ,  Gui-Hua Wang  1 ,  Bin Wang  1 ,  Lin-Li Lv  1 ,  Qiu-Li Wu  1 ,  Yi Wen  1 ,  Bi-Cheng Liu  4
Affiliations
  • 1. Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China.
  • 2. Department of Nephrology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
  • 3. Department of Nephrology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China. [email protected].
  • 4. Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China. [email protected].
PMID: 37225700 DOI: 10.1038/s41419-023-05854-5
Abstract

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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