Potential Mechanisms of the Ferroptosis Pathway in Iohexol-Induced Renal Injury

Abstract

Contrast-induced acute kidney damage (CI-AKI) is a common side effect of diagnostic imaging treatments that use iodinated contrast medium, such as Iohexol. This potential threat to renal function may cause irreversible damage, particularly through pathways such as ferroptosis. Ferroptosis is a regulated form of cell death that relies heavily on iron and reactive oxygen species. Using in vitro experiments with HK-2 cells, our study investigated the cytotoxic effects of Iohexol, with a particular focus on its potential involvement in the ferroptosis pathway. To counteract this, we synthesized poly(lactic-coglycolic acid) (PLGA) nanoparticles loaded with butyric acid and ferrostatin against ferroptosis-mediated cell damage. We assessed lipid peroxidation using malondialdehyde (MDA) assays, and measured superoxide dismutase (SOD) activity to evaluate oxidative stress. We employed electron microscopy to examine ultrastructural changes. We also investigated the involvement of the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2)/Heme Oxygenase-1 (HO-1) pathway, which plays a crucial role in preserving cellular oxidative balance. At concentrations above 100 mg/mL, Iohexol significantly reduced the viability of HK-2 cells. However, this impact was alleviated by butyric acid and ferrostatin PLGA nanoparticles, highlighting the critical role of ferroptosis. Iohexol caused a significant increase in MDA levels, indicating heightened lipid peroxidation. However, the ferrostatin effectively suppressed this effect. Ultrastructural analysis revealed characteristic morphological changes associated with ferroptosis, including mitochondrial swelling and cristae disappearance. Moreover, we uncovered a novel association between the G protein-coupled receptor 41 and the ferroptosis pathway. Furthermore, we observed a significant interplay with the Nrf2/HO-1 signaling pathway. In conclusion, our study provides insights into the complex molecular mechanisms involved in Iohexol-induced nephrotoxicity, with a specific emphasis on ferroptosis and Nrf2/HO-1 signaling. These findings serve as a basis for the development of potential therapeutic strategies targeting ferroptosis in the context of CI-AKI.