Protein kinase D1 modulates aldosterone-induced ENaC activity in a renal cortical collecting duct cell line.
Aldosterone treatment of M1-CCD cells stimulated an increase in epithelial Na(+) channel (ENaC) alpha-subunit expression that was mainly localized to the apical membrane. PKD1-suppressed cells constitutively expressed ENaCalpha at low abundance, with no increase after aldosterone treatment. In the PKD1-suppressed cells, ENaCalpha was mainly localized proximal to the basolateral surface of the epithelium both before and after aldosterone treatment. Apical membrane insertion of ENaCbeta in response to aldosterone treatment was also sensitive to PKD1 suppression as was the aldosterone-induced rise in the amiloride-sensitive, trans-epithelial current (I(TE)). The interaction of the mineralocorticoid receptor (MR) with specific elements in the promoters of aldosterone responsive genes is stabilized by ligand interaction and phosphorylation. PKD1 suppression inhibited aldosterone-induced SGK-1 expression. The nuclear localization of MR was also blocked by PKD1 suppression and MEK antagonism implicating both these kinases in MR nuclear stabilization. PKD1 thus modulates aldosterone-induced ENaC activity through the modulation of sub-cellular trafficking and the stabilization of MR nuclear localization.
McEneaney
Victoria
V
Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Smurfit Building, Beaumont Hospital, Dublin 9, Ireland.
Dooley
Ruth
R
Yusef
Yamil R
YR
Keating
Niamh
N
Quinn
Ursula
U
Harvey
Brian J
BJ
Thomas
Warren
W
D000450:Aldosterone / Q000494:pharmacology*; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D062708:Epithelial Sodium Channel Agonists; D053503:Epithelial Sodium Channels / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism*; D007685:Kidney Tubules, Collecting / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D021381:Protein Transport / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D018161:Receptors, Mineralocorticoid / Q000378:metabolism
D062708:Epithelial Sodium Channel Agonists; D053503:Epithelial Sodium Channels; D034741:RNA, Small Interfering; D018161:Receptors, Mineralocorticoid; D000450:Aldosterone; D000584:Amiloride; C089212:protein kinase D; D011493:Protein Kinase C