title: Aldosterone acutely stimulates NCC activity via a SPAK-mediated pathway.
abstract: Hypertension is a leading cause of morbidity and mortality worldwide, and disordered sodium balance has long been implicated in its pathogenesis. Aldosterone is perhaps the key regulator of sodium balance and thus blood pressure. The sodium chloride cotransporter (NCC) in the distal convoluted tubule of the kidney is a major site of sodium reabsorption and plays a key role in blood pressure regulation. Chronic exposure to aldosterone increases NCC protein expression and function. However, more acute effects of aldosterone on NCC are unknown. In our salt-abundant modern society where chronic salt deprivation is rare, understanding the acute effects of aldosterone is critical. Here, we examined the acute effects (12-36 h) of aldosterone on NCC in the rodent kidney and in a mouse distal convoluted tubule cell line. Studies demonstrated that aldosterone acutely stimulated NCC activity and phosphorylation without affecting total NCC abundance or surface expression. This effect was dependent upon the presence of the mineralocorticoid receptor and serum- and glucocorticoid-regulated kinase 1 (SGK1). Furthermore, STE20/SPS-1-related proline/alanine-rich kinase (SPAK) phosphorylation also increased, and gene silencing of SPAK eliminated the effect of aldosterone on NCC activity. Aldosterone administration via a minipump in adrenalectomized rodents confirmed an increase in NCC phosphorylation without a change in NCC total protein. These data indicate that acute aldosterone-induced SPAK-dependent phosphorylation of NCC increases individual transporter activity.
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois, USA. bko@uchicago.edu
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ko
authors.forename: Abinash C
authors.initials: AC
authors.lastname: Mistry
authors.forename: Lauren
authors.initials: L
authors.lastname: Hanson
authors.forename: Rickta
authors.initials: R
authors.lastname: Mallick
authors.forename: Brandi M
authors.initials: BM
authors.lastname: Wynne
authors.forename: Tiffany L
authors.initials: TL
authors.lastname: Thai
authors.forename: James L
authors.initials: JL
authors.lastname: Bailey
authors.forename: Janet D
authors.initials: JD
authors.lastname: Klein
authors.forename: Robert S
authors.initials: RS
authors.lastname: Hoover
mesh_terms: D000315:Adrenalectomy; D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D017874:Immediate-Early Proteins / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018161:Receptors, Mineralocorticoid / Q000187:drug effects; D049992:Sodium Chloride Symporters / Q000187:drug effects / Q000502:physiology*; D064486:Solute Carrier Family 12, Member 3 / Q000187:drug effects; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000450:Aldosterone; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D018161:Receptors, Mineralocorticoid; D049992:Sodium Chloride Symporters; D064486:Solute Carrier Family 12, Member 3; D000099184:Serum-Glucocorticoid Regulated Kinases; C578875:Slc12a3 protein, mouse; C116037:PAS domain kinases
keywords: NCC; SPAK; WNK4; aldosterone