Progression of experimental autoimmune encephalomyelitis (EAE) increases manganese superoxide dismutase (MnSOD) protein in the mitochondria of the mouse renal cortex

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Abstract Sodium has been implicated in the high NaCl diet-induced exacerbation of EAE. The kidney cortex is the primary site for regulating Na homeostasis. Reabsorption of Na by the cortex absolutely relies on the ATP-dependent Na,K-ATPase. Our previous studies demonstrated that the progression of EAE increases the Na,K-ATPase activity in the cortex even under normal salt intake. Mitochondrial respiration not only generates ATP, but also produces reactive oxygen species (ROS). As MnSOD is the first line of defense against the harmful effect of mitochondrial ROS, the present study analyzed whether EAE had any effects on MnSOD. Progression of EAE from mild to severe stage increased total MnSOD protein by 38% and had no significant effect on CuZnSOD protein. This effect was not explainable solely by the illness-induced reduction of water or food intake. Further analyses reveals that severe EAE increased mitochondrial MnSOD protein by 47%, Na,K-ATPase beta1 subunit protein by 64% with a concomitant increase of mitochondrial function as measured by the complex II activity and protein level of cytochrome oxidase 4, a major component of complex IV. Activation of Na,K-ATPase with two mechanistically different reagents, monensin and dexamethasone, simulates the effect of EAE on MnSOD protein in HEK293 cells. Fluorescent microscopic study showed that monensin and dexamethasone increased ROS in HEK293 cells, and this effect was inhibited by 400 U/ml catalase. Similarly, catalase also erased the effects of monensin and dexamethasone on MnSOD protein. In conclusion, progression of EAE increases mitochondrial MnSOD protein in the kidney cortex, likely due to the ROS produced during respiration to meet the demands of ATP for the Na,K-ATPase.