1. Academic Validation
  2. 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

  • 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

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. anita1685@163.com.
  • 4 Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China. liubc64@163.com.
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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