Realgar‐induced nephrotoxicity via ferroptosis in mice. Issue 11 (22nd July 2022)

• Record Type: Journal Article
• Authors: Zhang, Sheng; Cao, Shuai; Zhou, Heng; Li, Limin; Hu, Qing; Mao, Xiuhong; Ji, Shen
• Is Part Of: Journal of applied toxicology. Volume 42:Issue 11(2022)
• Page Start: 1843
• Page End: 1853
• Publication Date: 2022-07-22
• Subjects: ferroptosis -- HK2 cells -- mice -- nephrotoxicity -- Realgar; Toxicology -- Periodicals; Industrial toxicology -- Periodicals; Environmentally induced diseases -- Periodicals; Toxicology -- Periodicals; 615.9005
• DOI: 10.1002/jat.4362
• Languages: English
• ISSNs: 0260-437X

Abstract

Abstract: Ferroptosis is a novel form of iron‐dependent cell death that is involved in arsenic‐induced toxicity. Realgar is an arsenic‐containing Chinese medicine, which can result in nephrotoxicity because of long‐term exposure. However, it remains scientifically unknown whether Realgar is an inducer of ferroptosis in the kidney. This study investigated the role of ferroptosis in Realgar‐induced kidney toxicity in mice. ICR mice were exposed to Realgar for 28 days, and HK2 cells were exposed to Realgar in the presence or absence of treatment with ferrostatin‐1, a ferroptosis inhibitor. The ferroptosis‐related indicators were further evaluated. Realgar can cause nephrotoxicity in mice by continuous gavage for 28 days, accompanied by an increase in iron accumulation and reactive oxygen species (ROS). The reduced expression of Slc7A11 and Gpx4 further confirmed the ferroptosis mediated by Realgar. Meanwhile, Realgar disrupted the antioxidant system as evidenced by the formation of ROS leading to the inactivation of antioxidant enzymes. Realgar caused ferroptosis in a dose‐dependent manner, which was significantly reduced by ferrostatin‐1 in HK2 cells. This study revealed that Realgar‐induced ferroptosis triggered nephrotoxicity in mice and provided new clues to elucidate the mechanism of Realgar‐induced nephrotoxicity. Abstract : This study investigated the mechanism of Realgar‐induced nephrotoxicity. To the best of our knowledge, this work was the first to prove Realgar caused ferroptosis in a dose‐dependent manner in vivo and in vitro, accompanied by a disruption of the antioxidant system, which provided new clues to elucidate the mechanism of Realgar‐induced nephrotoxicity.