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Synthesis of the Na-K-ATPase -subunit is regulated at both the transcriptional and translational levels in IMCD3 cells

University of Colorado Health Sciences Center, Division of Renal Diseases and Hypertension, School of Medicine, Denver, Colorado

Submitted 27 January 2004 ; accepted in final form 14 September 2004

We previously reported that hypertonicity-mediated upregulation of the -subunit of Na-K-ATPase is dependent on both the JNK and the PI3 kinase pathways (Proc Natl Acad Sci USA 98: 13414, 2001). The present experiments were undertaken to explore the mechanisms whereby these pathways regulate the expression of the -subunit in inner medullary collecting duct cells (IMCD3). Inhibition of JNK with SP-600125 (20 µM), a concentration that causes an 95% inhibition of hypertonicity-stimulated JNK activation, markedly decreased the amount of the -subunit in response to 550 mosmol/kgH₂O for 48 h. This was accompanied by a parallel decrease in the -subunit mRNA. The rate at which the -subunit mRNA decreased was unaffected by actinomycin D. In contrast, inhibition of PI3 kinase with LY-294002 results in a marked decrease in the amount of -subunit protein but without alteration in -subunit message. The rate at which the -subunit protein decreased was unaffected by cyclohexamide. Transfection of IMCD3 cells with a -subunit construct results in the expression of both -subunit message and protein. However, in cortical collecting duct cells (M1 cells) such transfection resulted in expression of only the message and not the protein. We conclude that JNK regulates the -subunit at the transcriptional level while PI3 kinase regulates -subunit expression at the translational level. There is also posttranscriptional cell specificity in the expression of the -subunit of Na-K-ATPase.

osmoregulation; hypertonicity

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