Inhibition of eIF5A hypusination enhances antioxidant defense to prevent kidney Ischemia/Reperfusion injury.

Abstract

Ischemia/reperfusion (I/R) refers to the interruption or reduction of blood flow followed by its sudden restoration, resulting in significant oxidative stress, particularly in the kidneys, which are highly oxygen-dependent and metabolically active. During I/R, excessive production of reactive oxygen species (ROS) is triggered by mitochondrial dysfunction and activation of oxidases. Cellular antioxidant defences which attempt to neutralise ROS can become overwhelmed, resulting in oxidative stress that damages macromolecules and ultimately impairs cell function and survival. In kidney transplantation, ROS-induced I/R injury contributes to delayed graft function and chronic graft loss. In this context, inhibition of eIF5A hypusination using the deoxyhypusine synthase inhibitor GC7 protects kidney against I/R injury, potentially by reducing oxidative stress. However, the exact mechanisms and dynamics of this antioxidant protection remain to be elucidated. Using a mouse model of renal I/R and equivalent in vitro cell model, we analyzed the concomitance between protection against oxidative stress due to GC7 treatment and recovery of renal function or cell survival. In addition, we analyzed proteome modulation due to GC7 treatment to unravel pathways involved in its protective effect, and we defined the impact of GC7 on ROS productions and on antioxidant defences. We demonstrated that GC7 protected against I/R-induced injury and anoxia/reoxygenation in both in vivo and in vitro models by conditioning the cells and organ to resist stress. From a mechanistic point of view, we showed that the protective effects of GC7 were largely attributed to the enhancement of antioxidant defences, mainly through sustained catalase activity, which was mandatory in kidney cells to survive in the face of ROS production. Overall, GC7 is a clinical candidate for reducing oxidative damage in kidney transplantation, particularly for organs from marginal donors. Its ability to reprogram redox and metabolic pathways early after treatment supports its use to improve graft survival and function.