Biotechnology and Bioprocess Engineering 2024; 29(5): 833-844  
Pre-activation of hypoxia-inducible factor 1-α using prolyl hydroxylase domain inhibitors reduces cisplatin-induced nephrotoxicity
Bomin Kim1,2 · Soonjo Kwon1,2
1 Department of Biological Engineering, Inha University, Incheon 22212, Korea
2 Department of Biological Sciences and Bioengineering, Inha University, Incheon 22212, Korea
Correspondence to: ✉ Soonjo Kwon
soonjo.kwon@inha.ac.kr
Received: January 8, 2024; Revised: June 13, 2024; Accepted: June 17, 2024; Published online: June 22, 2024.
© The Korean Society for Biotechnology and Bioengineering. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Cisplatin is a widely used, highly effective chemotherapy drug that has a critical nephrotoxic side effect associated with acute kidney injury. Hypoxia pre-treatment is one of the methods used to reduce cisplatin-induced renal toxicity, but the exact cellular process associated with this protective effect is not clearly understood. Hypoxia-inducible factor 1 alpha (HIF-1α), the main transcription factor under hypoxia, may play a crucial role in this protective effect. To verify this, the degree of HIF-1α activation was investigated. Renal proximal tubular epithelial cells (HK-2) were treated with cisplatin following exposure to FG-4592 and CoCl2, prolyl hydroxylase domain (PHD) inhibitors that stabilize HIF-1α. Roxadustat (FG-4592) is a PHD inhibitor recently approved by the European medicines agency (EMA) for the treatment of anemia. Hypoxia pre-treatment with PHD inhibitors presented a protective effect against cisplatin-induced kidney injury. In addition, hypoxia pre-treatment relieved oxidative stress by hypoxia response genes sufficiently expressed under hypoxic pre-conditions. In conclusion, we investigated the correlation between the degree of HIF-1α pre-activation and the reduction in cisplatin-induced nephrotoxicity using PHD inhibitors. This study extends the applicability of PHD inhibitors as palliators of cisplatin-induced nephrotoxicity and provides valuable insights into overcoming the limitations of cisplatin use.
Keywords: Hypoxia · Kidney injury · Nephrotoxicity · Cisplatin · Prolyl hydroxylase domain inhibitor · Roxadustat

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