Clinical and experimental nephrology · 2026
5-hydroxy-1-methylhydantoin (NZ-419), an endogenous antioxidant, attenuates mycotoxin-induced oxidative stress in human kidney proximal tubular epithelial cells.
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Ofori-Attah Ebenezer, Hashimoto Mai, Oki Mayu, Kansui Hisao, Maeda Hitoshi, Okazaki Shoko, Takeshita Keizo, Kadowaki Daisuke
Аннотация
BACKGROUND: Exposure to foodborne mycotoxins such as ochratoxin A (OTA) and citrinin (CIT) causes severe oxidative stress-mediated nephropathy. This study investigated the protective potential of 5-hydroxy-1-methylhydantoin (NZ-419), an endogenous creatinine metabolite, against OTA- and CIT-induced toxicity in human proximal tubular epithelial (HK-2) cells.
METHODS: We evaluated the radical-scavenging activity of NZ-419 using cell-free assays, including electron spin resonance. In HK-2 cells, its effects on mycotoxin-induced cytotoxicity, reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP), and related signaling pathways were assessed using biochemical assays, Western blotting, and qPCR. The effects of NZ-419 on hypoxia-reoxygenation-induced cellular stress were also examined.
RESULTS: NZ-419 selectively scavenged hydroxyl radicals and peroxynitrite. In HK-2 cells, it significantly attenuated OTA-induced cytotoxicity. While not fully restoring viability in CIT-treated cells, it effectively mitigated oxidative stress induced by both mycotoxins. NZ-419 prevented MMP depolarization and upregulated Bcl-2, indicating anti-apoptotic potential. It suppressed ROS overproduction and NADPH oxidase 4 (NOX4) expression while activating the Keap1-Nrf2 pathway, upregulating antioxidant genes (SOD1, CAT, and GPx). Furthermore, NZ-419 reduced HIF-1α and CTGF expression under both mycotoxin-induced and hypoxia-reoxygenation conditions.
CONCLUSION: NZ-419 selectively scavenges toxic radicals and attenuates mycotoxin-induced oxidative stress and mitochondrial dysfunction in HK-2 cells. These findings provide mechanistic evidence for the protective effects of NZ-419 and support its potential as a renoprotective agent against oxidative stress-related kidney injury.
METHODS: We evaluated the radical-scavenging activity of NZ-419 using cell-free assays, including electron spin resonance. In HK-2 cells, its effects on mycotoxin-induced cytotoxicity, reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP), and related signaling pathways were assessed using biochemical assays, Western blotting, and qPCR. The effects of NZ-419 on hypoxia-reoxygenation-induced cellular stress were also examined.
RESULTS: NZ-419 selectively scavenged hydroxyl radicals and peroxynitrite. In HK-2 cells, it significantly attenuated OTA-induced cytotoxicity. While not fully restoring viability in CIT-treated cells, it effectively mitigated oxidative stress induced by both mycotoxins. NZ-419 prevented MMP depolarization and upregulated Bcl-2, indicating anti-apoptotic potential. It suppressed ROS overproduction and NADPH oxidase 4 (NOX4) expression while activating the Keap1-Nrf2 pathway, upregulating antioxidant genes (SOD1, CAT, and GPx). Furthermore, NZ-419 reduced HIF-1α and CTGF expression under both mycotoxin-induced and hypoxia-reoxygenation conditions.
CONCLUSION: NZ-419 selectively scavenges toxic radicals and attenuates mycotoxin-induced oxidative stress and mitochondrial dysfunction in HK-2 cells. These findings provide mechanistic evidence for the protective effects of NZ-419 and support its potential as a renoprotective agent against oxidative stress-related kidney injury.