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Akt Inhibition as Preconditioning Treatment to Protect Kidney Cells against Anoxia
Nicolas Melis1, Romain Carcy2,3,4, Isabelle Rubera2,4
1Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
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.
Insights
Inhibiting Akt kinase protects kidney cells from ischemia/reperfusion injury by reducing mitochondrial ROS. This finding suggests Akt inhibition as a novel preconditioning strategy for kidney protection.
Area of Science:
- Nephrology
- Pathophysiology
- Cellular Biology
Background:
- Ischemia/reperfusion (I/R) injury poses a significant threat to kidney function due to high oxygen demand and limited regeneration.
- Previous research indicated that targeting the hypusination pathway of eIF5A with GC7 enhances ischemic tolerance, particularly in kidney transplantation.
- Akt signaling is implicated in both ischemic protection and glucose metabolism, suggesting a potential link with GC7's effects.
Purpose of the Study:
- To investigate the relationship between GC7, Akt signaling, and kidney cell protection against anoxia and myxothiazol-induced stress.
- To evaluate the efficacy of direct Akt inhibition as a preconditioning strategy for enhancing kidney cell tolerance to ischemic injury.
Main Methods:
- Utilized proximal kidney cells exposed to anoxia or myxothiazol.
- Administered GC7 and assessed its impact on Akt phosphorylation at Ser473 and Thr308.
- Investigated the protective effects of direct Akt inhibitors on kidney cells subjected to ischemic conditions and myxothiazol.
Main Results:
- GC7 treatment led to decreased Akt phosphorylation at key regulatory sites (Ser473 and Thr308).
- Direct inhibition of Akt provided significant protection to kidney cells against both ischemia and myxothiazol.
- The pro-survival effect of Akt inhibitors was reversible, associated with reduced mitochondrial reactive oxygen species (ROS) production, but not with altered metabolism or antioxidant defense.
Conclusions:
- Akt inhibition serves as an effective preconditioning treatment against kidney ischemia.
- Targeting Akt signaling offers a promising avenue for developing strategies to mitigate I/R injury in the kidneys.
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