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

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.

• Authors: Zuo-Lin Li, Lin Ding, Rui-Xia Ma, Yue Zhang, Yi-Lin Zhang, Wei-Jie Ni, Tao-Tao Tang, Gui-Hua Wang, Bin Wang, Lin-Li Lv, Qiu-Li Wu, Yi Wen, Bi-Cheng Liu
• Journal: Cell death & disease (Cell Death Dis) Vol. 14 Issue 5 Pg. 339 (05 24 2023) ISSN: 2041-4889 [Electronic] England
• PMID: 37225700 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023. The Author(s).

Chemical References

• Hexokinase
• Hypoxia-Inducible Factor 1, alpha Subunit
• Hif1a protein, mouse
• hexokinase 2, mouse

Topics

• Animals
• Mice
• Disease Models, Animal
• Hexokinase (genetics)
• Hypoxia (complications)
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics)
• Kidney
• Mitophagy
• Reperfusion Injury
• Transcriptional Activation