1,3-Dichloro-2-propanol-Induced Renal Tubular Cell Necroptosis through the ROS/RIPK3/MLKL Pathway

Abstract

1,3-Dichloro-2-propanol (1,3-DCP), as a food pollutant, exists in a variety of foods. Studies have shown that it has nephrotoxicity. In the study, we found that 1,3-DCP caused renal injury with necroptosis in C57BL/6J mice. The mechanism of 1,3-DCP-caused nephrotoxicity was further explored in NRK-52E cells in vitro. We found that 1,3-DCP caused cell necroptosis with the increase in lactate dehydrogenase (LDH) levels and the expressions of RIPK3 and MLKL. But pretreatment with a ROS inhibitor Nacetyl-L-cysteine (NAC), a RIPK3 inhibitor GSK'872, or RIPK3 gene silencing alleviated 1,3-DCP-induced cell necroptosis. The data indicated that 1,3-DCP induced necroptosis through the ROS/RIPK3/MLKL pathway in NRK-52E cells. In further mechanistic studies, we explored how 1,3-DCP induced ROS production. We found that 1,3-DCP inhibited the expressions of nuclear and cytoplasmic Nrf2. But pretreatment with an Nrf2 activator dimethyl fumarate (DMF) up-regulated the expressions of nuclear and cytoplasmic Nrf2 and down-regulated ROS levels and RIPK3 and MLKL expressions. We also examined the effects of mitophagy on 1,3-DCP-induced ROS. The data manifested that 1,3-DCP suppressed mitophagy in NRK-52E cells by decreasing LC3-II, Pink1, and Parkin levels, increasing p62 levels, and decreasing colocalization of LC3 and Mito-Tracker Red. Pretreatment with an autophagy activator rapamycin (Rapa) decreased 1,3-DCP-induced ROS. Taken together, our data identified that 1,3-DCP caused renal necroptosis through the ROS/RIPK3/MLKL pathway.

Acer truncatum Bunge seed oil ameliorated oxaliplatin-induced demyelination by improving mitochondrial dysfunction via the Pink1/Parkin mitophagy pathway

“…Yu et al demonstrated that the autophagy activator Rapa improved mitochondrial function by the activation of mitophagy and restoration of autophagy flow via Pink1/Parkin in 1,3-dichloro-2-propanol-caused renal tubular cell injury. 55 Fan et al found that ginsenoside CK improved skeletal muscle insulin resistance by activating Pink1/Parkin-induced mitophagy and restoring Pink1/Parkin-enhanced autophagy flow. 56 In our previous study, we determined that linolenic acid ameliorated mitochondrial function in C. elegans with sarcopenia by inducing Pink1/Parkin-mediated mitochondrial autophagy.…”

Monacolin K Induces Apoptosis of Human Glioma U251 Cells by Triggering ROS-Mediated Oxidative Damage and Regulating MAPKs and NF-κB Pathways

“…Green fluorescence indicates the presence of ROS in the cells . They react with biological compounds, leading to metabolic pathway changes, cell membrane peroxidation, oxidative protein modification, and DNA mutations that promote cell or tissue damage . Their elevated intracellular levels are sufficient to trigger apoptosis and can drive cancer cells to the edge of the toxicity threshold. , In cancer, high levels of ROS can trigger oxidative stress, which further leads to cell cycle arrest, senescence, and apoptosis .…”

Mitophagy-related regulated cell death: molecular mechanisms and disease implications

“…In alcoholic liver disease, tetramethylpyrazine (TMP)-induced activation of PINK1-Parkin-mediated mitophagy has been reported to reduce the generation of mtROS, which inhibits the activation of necrosomes to suppress MLKL-dependent necroptosis [ 55 ]. In contrast, inhibition of PINK1-Parkin-mediated mitophagy by 1,3-dichloro-2-propanol (1,3-DCP) can induce renal tubular cell necroptosis through the ROS/RIPK3/MLKL axis [ 56 ]. In addition, studies have shown that mPTP opening signaling pathways can be inhibited by activating mitophagy [ 57 – 59 ], which may represent another mtROS-independent mechanism by which mitophagy inhibits necroptosis.…”