부산대학교 도서관

Aquaporin-8 (AQP8) is a peroxiporin, a transmembrane water and hydrogen peroxide (H 2 O 2) transport protein expressed in the mitochondrial and plasma membranes of pancreatic β-cells. AQP8 protein expression is low under physiological conditions, but it increases after cytokine exposure both, in vitro and in vivo , possibly related to a NF-κB consensus sequence in the promoter. AQP8 knockdown (KD) insulin-producing RINm5F cells are particularly susceptible to cytokine-mediated oxidative stress. Cytokine (a mixture of IL-1β, TNF-α, and IFN-γ) treated AQP8 KD cells exhibited pronounced sensitivity to reactive oxygen and nitrogen species (ROS and RNS), resulting in a significant loss of β-cell viability due to enhanced toxicity of the increased concentrations of H 2 O 2 and hydroxyl radicals (●OH) in mitochondria of AQP8 KD cells. This viability loss went along with increased caspase activities, reduced nitrite concentration (representative of nitric oxide (NO●) accumulation) and increased lipid peroxidation. The explanation for the increased toxicity of the proinflammatory cytokines in AQP8 KD cells resides in the fact that efflux of the H 2 O 2 generated during oxidative stress in the β-cell mitochondria is hampered through the loss of the peroxiporin channels in the mitochondrial membranes of the AQP8 KD cells. The increased proinflammatory cytokine toxicity due to loss of AQP8 expression in the KD β-cell mitochondria is thus the result of increased rates of apoptosis. This decreased cell viability is caused by increased levels of oxidative stress along with a ferroptosis-mediated cell death component due to decreased NO● generation. The schematic pieces were provided by Smart Medical Art and adapted (https://smart.servier.com/image-set-download/). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License. [Display omitted] • IL-1β mediates AQP8 overexpression in pancreatic β-cells, possibly via a NF-κB consensus sequence in the promoter. • AQP8 expression reduces cytokine toxicity to β-cells by transporting H 2 O 2 out of the mitochondrial site of origin. • AQP8 KD increases cytokine toxicity by ●OH radicals formed as a result of increased mitochondrial H 2 O 2 generation. [ABSTRACT FROM AUTHOR]