Nrf2-akt interactions regulate heme oxygenase 1 expression in kidney epithelia during hypoxia and hypoxia-reoxygenation.

NRF2-AKT INTERACTIONS REGULATE HEME OXYGENASE 1 EXPRESSION IN KIDNEY EPITHELIA DURING HYPOXIA AND HYPOXIA-REOXYGENATION. Am J Physiol Renal Physiol. 2016 Aug 31;:ajprenal.00362.2016 Authors: Reddy Potteti H, Reddy Tamatam C, Marreddy R, Reddy NM, Noel S, Rabb H, Reddy SP Abstract Ischemia-reperfusion (IR)-induced kidney injury is a major clinical problem, but the underlying mechanisms remain unclear. The transcription factor Nuclear Factor, Erythroid 2-like 2 (NFE2L2 or Nrf2) is crucial for protection against oxidative stress generated by pro-oxidant insults. We have previously shown that Nrf2 deficiency enhances susceptibility to IR-induced kidney injury in mice and its upregulation is protective. Here, we examined Nrf2 target antioxidant gene expression and the mechanisms of its activation in both human and murine kidney epithelia following acute (2 h) and chronic (12 h) hypoxia and re-oxygenation conditions. We found that acute hypoxia modestly and chronic hypoxia strongly stimulates Nrf2 putative target HMOX1 expression, but not other antioxidant genes. Inhibition of AKT1/2 or ERK1/2 signaling blocked this induction; AKT1/2 but not ERK1/2 inhibition affected Nrf2 levels in basal state and acute hypoxia-reoxygenation. Unexpectedly, chromatin immunoprecipitation assays revealed reduced levels of Nrf2 binding at the distal AB1 and SX2 enhancers and proximal promoter of HMOX1 in acute hypoxia, accompanied by diminished levels of nucl...
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Tags: Am J Physiol Renal Physiol Source Type: research