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.
Highlights
Acute kidney injury (AKI) imposes a significant burden on the health care system as it affects more than 13 million people globally and is associated with increased morbidity, prolonged hospitalizations, and mortality [1,2,3]
Since TonEBP is induced by hypoxia [19] and ischemic injury in the kidney is characterized by necroinflammation [5], we asked whether TonEBP played a role in the
Male B57BL/6 mice were subjected to a 30 min bilateral renal ischemia followed by reperfusion (I/R) forby
Summary
Acute kidney injury (AKI) imposes a significant burden on the health care system as it affects more than 13 million people globally and is associated with increased morbidity, prolonged hospitalizations, and mortality [1,2,3]. Renal ischemia is a common cause of AKI along with sepsis and cisplatin treatment [4]. Kidney tubules are highly susceptible to ischemic injury and much of the cellular pathways involved have been delineated in recent years [5]. Ischemia causes local inflammation which is tightly linked to the necrosis: so called necroinflammation in which cellular injury and inflammation are reciprocally enhanced in an autoamplification loop [5]. Understanding molecular pathways leading to necroinflammation would be critical for developing therapeutic strategies for AKI
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