HIF in Nephrotoxicity during Cisplatin Chemotherapy: Regulation, Function and Therapeutic Potential

SIMPLE SUMMARY: Cisplatin is a widely used chemotherapy drug, but its use and efficacy are limited by its nephrotoxicity. HIF has protective effects against kidney injury during cisplatin chemotherapy, but it may attenuate the anti-cancer effect of cisplatin. In this review, we describe the role and regulation of HIF in cisplatin-induced nephrotoxicity and highlight the therapeutic potential of targeting HIF in chemotherapy. ABSTRACT: Cisplatin is a highly effective, broad-spectrum chemotherapeutic drug, yet its clinical use and efficacy are limited by its side effects. Particularly, cancer patients receiving cisplatin chemotherapy have high incidence of kidney problems. Hypoxia-inducible factor (HIF) is the “master” transcription factor that is induced under hypoxia to trans-activate various genes for adaptation to the low oxygen condition. Numerous studies have reported that HIF activation protects against AKI and promotes kidney recovery in experimental models of cisplatin-induced acute kidney injury (AKI). In contrast, little is known about the effects of HIF on chronic kidney problems following cisplatin chemotherapy. Prolyl hydroxylase (PHD) inhibitors are potent HIF inducers that recently entered clinical use. By inducing HIF, PHD inhibitors may protect kidneys during cisplatin chemotherapy. However, HIF activation by PHD inhibitors may reduce the anti-cancer effect of cisplatin in tumors. Future studies should test PHD inhibitors in tumor-bearing animal models to verify their effects in kidneys and tumors.