Nrf2-mediated chromatin activation of hyperosmotic response genes attenuates heat-induced renal injury [ChIP-seq]

The escalating frequency and duration of extreme weather events, driven by ongoing climate change, are heightening health hazards associated with heat stress. Heat stress can cause whole-body hyperosmolarity and increase risk of chronic kidney disease. Here, we confirmed Nrf2 as the core transcription factor for cellular resistance to hyperosmotic stress through drug screening. Meanwhile, we constructed a mouse model of renal injury caused by high temperature dehydration, genetic deletion of Nrf2 further increased the renal injury and fibrosis. The natural compound SFN, found in cruciferous plants, can be used to activate Nrf2 and alleviate kidney damage caused by high-temperature dehydration. Mechanistically, we performed hyperosmotic stress in kidney collecting duct cells, and through ATAC-seq and ChIP-seq analysis of multiple histone modifications, found that most of the hyperosmotic response genes changed their chromatin state after pharmacological activation of Nrf2. The activation of the chromatin state in hyperosmotic response genes enhances the binding affinity of Nfat5 following exposure to hyperosmotic stress. Together, activation of Nrf2 maintains the active chromatin state of hyperosmotic response genes. Under hyperosmotic stress, the core transcription factor Nfat5 efficiently activates gene expression, thereby assisting cells in resisting hyperosmotic stress. Additionally, activation of Nrf2 by SFN may serve as a potential therapeutic approach for preventing renal injury caused by high-temperature dehydration.