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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Stimulation of Na,K-ATPase by low potassium requires reactive oxygen species

¹Department of Medicine, Uniformed Services University, Bethesda 20814; ²Department of Medicine, University of Maryland, Baltimore, Maryland 21201; and ³Department of Natural Environment Sciences, Kyoto University, Kyoto 606-01, Japan

Submitted 19 November 2002 ; accepted in final form 2 April 2003

The signaling pathway that transduces the stimulatory effect of low K⁺ on the biosynthesis of Na,K-ATPase remains largely unknown. The present study was undertaken to examine whether reactive oxygen species (ROS) mediated the effect of low K⁺ in Madin-Darby canine kidney (MDCK) cells. Low K⁺ increased ROS activity in a time- and dose-dependent manner, and this effect was abrogated by catalase and N-acetylcysteine (NAC). To determine the role of ROS in low-K⁺-induced gene expression, the cells were first stably transfected with expression constructs in which the reporter gene chloramphenicol acetyl transferase (CAT) was under the control of the avian Na,K-ATPase -subunit 1.9 kb and 900-bp 5'-flanking regions that have a negative regulatory element. Low K⁺ increased the CAT expression in both constructs. Catalase or NAC inhibited the effect of low K⁺. To determine whether the increased CAT activity was mediated through releasing the repressive effect or a direct stimulation of the promoter, the cells were transfected with a CAT expression construct directed by a 96-bp promoter fragment that has no negative regulatory element. Low K⁺ also augmented the CAT activity expressed by this construct. More importantly, both catalase and NAC abolished the effect of low K⁺. Moreover, catalase and NAC also inhibited low-K⁺-induced increases in the Na,K-ATPase ₁- and ₁-subunit protein abundance and ouabain binding sites. The antioxidants had no significant effect on the basal levels of CAT activity, protein abundance, or ouabain binding sites. In conclusion, low K⁺ enhances the Na,K-ATPase gene expression by a direct stimulation of the promoter activity, and ROS mediate this stimulation and also low-K⁺-induced increases in the Na,K-ATPase protein contents and cell surface molecules.

Madin-Darby canine kidney cells; N-acetylcysteine; catalase

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