Transcriptional Regulator TonEBP Mediates Oxidative Damages in Ischemic Kidney Injury

Abstract

TonEBP (tonicity-responsive enhancer binding protein) is a transcriptional regulator whose expression is elevated in response to various forms of stress including hyperglycemia, inflammation, and hypoxia. Here we investigated the role of TonEBP in acute kidney injury (AKI) using a line of TonEBP haplo-deficient mice subjected to bilateral renal ischemia followed by reperfusion (I/R). In the TonEBP haplo-deficient animals, induction of TonEBP, oxidative stress, inflammation, cell death, and functional injury in the kidney in response to I/R were all reduced. Analyses of renal transcriptome revealed that genes in several cellular pathways including peroxisome and mitochondrial inner membrane were suppressed in response to I/R, and the suppression was relieved in the TonEBP deficiency. Production of reactive oxygen species (ROS) and the cellular injury was reproduced in a renal epithelial cell line in response to hypoxia, ATP depletion, or hydrogen peroxide. The knockdown of TonEBP reduced ROS production and cellular injury in correlation with increased expression of the suppressed genes. The cellular injury was also blocked by inhibitors of necrosis. These results demonstrate that ischemic insult suppresses many genes involved in cellular metabolism leading to local oxidative stress by way of TonEBP induction. Thus, TonEBP is a promising target to prevent AKI.

High blood sugar may blunt the protective benefits of FXR for the survival of renal medullary collecting duct cells in response to hypertonic stress

“…However, in this experiment, we showed that FXR protection of the renal collecting duct cells after dehydration was weakened under high glucose conditions. According to previous studies, the lack of water caused a hypertonic environment of kidney tissue, and then oxidative stress response [23]. Our results proved that FXR triggered gp91 transcription in the renal cortex after dehydration in a non-high-glucose environment.…”

“…Therefore, we saw decreased urinary concentration and ltration in diabetic mice after water deprivation. Some data show that high osmotic stress and overexpression of TonEBP were linked with high oxidative stress damage in the kidney [23]. In this experiment, immuno uorescence detection showed that gp91 was highly expressed in the medulla after water withdrawal, which was consistent with the high expression of TonEBP.…”

“…TonEBP, also known as NFAT5, is the only known gene regulator of the mammalian adaptive response to osmotic stress [22]. In the hypertonic state, the activation of TonEBP causes oxidative stress [23]. Recent data show that in the renal medulla TonEBP expression is driven by FXR and its nuclear translocation potentiates its osmoprotective role [11].…”