TonEBP/OREBP is activated by hypoxia: Role in renal Ischemia and Reperfusion

The present paradigm describe that hypertonicity in the kidney medulla increases activity of the transcription factor TonEBP/OREBP, resulting in cell protection. Additionally, kidney medulla is also hypoxic (10–18mmHg), however there is not information about the effect of hypoxia on TonEBP/OREBP. Using in vivo and in vitro models, we evaluate the effect of low partial pressure of oxygen (PaO 2 ) on TonEBP/OREBP activity. We find that 1) Reduction in PaO 2 increased the TonEBP/OREBP expression in primary cell culture from medulla of rat kidney and HEK293 cells. 2) Anoxia increased the transcriptional activity and nuclear translocation of TonEBP/OREBP in HEK293 cells. 3) TonEBP/OREBP Knock down increased the cell death induced by hypoxia. 4) TonEBP/OREBP and HIF‐1α expression were increased in kidney (cortex and medulla) from rat subjected to experimental model of ischemic and reperfusion (I/R). 5) Experimental I/R increased the TonEBP/OREBP‐target gene aldose reductase (AR). 6) TonEBP/OREBP activators, ATM and p110α, were induced in rat kidney (cortex and medulla) in the same timing of TonEBP/OREBP. These results demonstrate by first time the TonEBP/OREBP is induced by hypoxia and it has a potential protective role against ischemic damage.