Akt Inhibition as Preconditioning Treatment to Protect Kidney Cells against Anoxia.

Didier F Pisani,Isabelle Rubera,Nicolas Melis,Christophe Duranton,Romain Carcy,Marc Cougnon,Michel Tauc

doi:10.3390/ijms23010152

Abstract

Lesions issued from the ischemia/reperfusion (I/R) stress are a major challenge in human pathophysiology. Of human organs, the kidney is highly sensitive to I/R because of its high oxygen demand and poor regenerative capacity. Previous studies have shown that targeting the hypusination pathway of eIF5A through GC7 greatly improves ischemic tolerance and can be applied successfully to kidney transplants. The protection process correlates with a metabolic shift from oxidative phosphorylation to glycolysis. Because the protein kinase B Akt is involved in ischemic protective mechanisms and glucose metabolism, we looked for a link between the effects of GC7 and Akt in proximal kidney cells exposed to anoxia or the mitotoxic myxothiazol. We found that GC7 treatment resulted in impaired Akt phosphorylation at the Ser473 and Thr308 sites, so the effects of direct Akt inhibition as a preconditioning protocol on ischemic tolerance were investigated. We evidenced that Akt inhibitors provide huge protection for kidney cells against ischemia and myxothiazol. The pro-survival effect of Akt inhibitors, which is reversible, implied a decrease in mitochondrial ROS production but was not related to metabolic changes or an antioxidant defense increase. Therefore, the inhibition of Akt can be considered as a preconditioning treatment against ischemia.

Highlights

Ischemia/reperfusion (I/R) is characterized by an interruption in the blood supply to tissues or organs, which leads to oxygen and nutrient deprivation and to a sudden and acute reoxygenation and nutrient availability [1,2]
We have previously shown the high effectiveness of GC7 pretreatment, a specific and reversible eIF5A hypusination inhibitor, in protecting the kidney from ischemia situations and proximal convoluted tubule cells (PCT) from anoxia [41]
GC7 pretreatment for 24 h induced inhibition of Akt phosphorylation at both Ser473 and Thr308 sites (Figure 1A). To determine if this inhibition could be considered as a preconditioning event mimicking a stress response, PCT cells were deprived of nutrients in minimum media (MM) for 30 min either maintained under normoxia or exposed to anoxia to mimic an acute ischemic event

Summary

Introduction

Ischemia/reperfusion (I/R) is characterized by an interruption in the blood supply to tissues or organs, which leads to oxygen and nutrient deprivation and to a sudden and acute reoxygenation and nutrient availability [1,2]. This ischemic stress, which occurs in pathological situations (stroke, myocardial infarction) and during operations with voluntary blood arrest (organ transplantation, cardiovascular surgery), can lead to cell death and irreversible ischemic lesions [1]. I/R generates a two-stage oxidative stress characterized by an overproduction of reactive oxygen species (ROS), which causes irreversible oxidation of biological molecules leading to cell death [6]

Methods

Results

Conclusion