The importance of aquaporin-8 for cytokine-mediated toxicity in rat insulin-producing cells

Aquaporin-8 (AQP8) is a peroxiporin, a transmembrane water and hydrogen peroxide (H2O2) transport protein expressed in the mitochondrial and plasma membranes of pancreatic beta-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-Kappa B 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-1 beta, TNF-alpha, and IFN-gamma) treated AQP8 KD cells exhibited pronounced sensitivity to reactive oxygen and nitrogen species (ROS and RNS), resulting in a significant loss of beta-cell viability due to enhanced toxicity of the increased concentrations of H2O2 and hydroxyl radicals ((OH)-O-center dot) in mitochondria of AQP8 KD cells. This viability loss went along with increased caspase activities, reduced nitrite concentration (representative of nitric oxide (NO center dot) 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 H2O2 generated during oxidative stress in the beta-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 beta-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 center dot generation.

Automated summary

Aquaporin-8 (AQP8) is a peroxiporin protein expressed in the mitochondrial and plasma membranes of pancreatic beta-cells. AQP8 knockdown cells exhibit increased sensitivity to proinflammatory cytokines, leading to enhanced oxidative stress and decreased cell viability due to decreased nitric oxide (NO center dot) generation.