The kidney-specific WNK1 isoform is induced by aldosterone and stimulates epithelial sodium channel-mediated Na+ transport.
WNK1 belongs to a unique family of Ser/Thr kinases that have been implicated in the control of blood pressure. Intronic deletions in the WNK1 gene result in its overexpression and lead to pseudohypoaldosteronism type II, a disease with salt-sensitive hypertension and hyperkalemia. How overexpression of WNK1 leads to Na(+) retention and hypertension is not entirely clear. Similarly, there is no information on the hormonal regulation of expression of WNK kinases. There are two main WNK1 transcripts expressed in the kidney: the originally described "long" WNK1 and a shorter transcript that is specifically expressed in the kidney (KS-WNK1). The goal of this study was to determine the effect of aldosterone, the main hormonal regulator of Na(+) homeostasis, on the transcription of WNK1 isoforms in renal target cells, by using an unique mouse cortical collecting duct cell line that stably expresses functional mineralocorticoid receptors. Our results demonstrate that aldosterone, at physiological concentrations, rapidly induces the expression of the KS-WNK1 but not that of the long-WNK1 in these cells. Importantly, stable overexpression of KS-WNK1 significantly increases transepithelial Na(+) transport in cortical collecting duct cells. Similarly, coexpression of KS-WNK1 and the epithelial Na(+) channel in Fischer rat thyroid epithelial cells also stimulates Na(+) current, suggesting that KS-WNK1 affects the subcellular location or activity but not the expression of epithelial Na(+) channel. These observations suggest that stimulation of KS-WNK1 expression might be an important element of aldosterone-induced Na(+) retention and hypertension.
Náray-Fejes-Tóth
Anikó
A
Department of Physiology, Dartmouth Medical School, Lebanon, NH 03756, USA. aniko-fejes-toth@dartmouth.edu
Snyder
Peter M
PM
Fejes-Tóth
Géza
G
D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D017136:Ion Transport / Q000187:drug effects; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D015778:Minor Histocompatibility Antigens; D009928:Organ Specificity; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000378:metabolism*; D000076204:WNK Lysine-Deficient Protein Kinase 1
D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D015778:Minor Histocompatibility Antigens; D012333:RNA, Messenger; D015222:Sodium Channels; D000450:Aldosterone; D003907:Dexamethasone; D012964:Sodium; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498743:WNK1 protein, human; C498744:Wnk1 protein, mouse; C410410:Wnk1 protein, rat