Pre-activation of hypoxia-inducible factor 1-α using prolyl hydroxylase domain inhibitors reduces cisplatin-induced nephrotoxicity

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.