Abstract
Organ transplantation is limited by organ donation and the inevitable I/R injury associated with organ preservation. To date, little clinical advancements in I/R injury have been made because the basic molecular mechanisms remain poorly understood. The objective was to characterize the role of ezrin in preservation injury since it is hypothesized that the sub‐lamellar cytoskeletal system is an important mediator of ischemic injury. Ezrin dissociates from the cytoskeletal structures during cold ischemia in renal tubules. In LLC‐PK1 cells, preservation injury is exacerbated with ezrin knock‐down (siRNA) and attenuated with ezrin over expression. Point mutations of ezrin at T567A potentiated whereas T567D attenuated preservation injury when expressed in LLC‐PK1 cells, implicating the binding functionality of ezrin as important for protection. Specific ezrin binding sites were also identified on purified mitochondria from renal tubules and exogenous recombinant ezrin attenuated the sensitivity of the mitochondrial permeability transition pore to calcium. Finally, dissociation of the ezrin analog moesin in liver and sinusoidal endothelial cells was also observed with preservation. In conclusion, ezrin plays an important causal role in I/R injury via its linker functionality and possibly by a novel mitochondrial binding role. Supported by NIH R01 DK087737.
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