Aldosterone acutely stimulates NCC activity via a SPAK-mediated pathway

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 tubul...

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Veröffentlicht in:American journal of physiology. Renal physiology 2013-09, Vol.305 (5), p.F645-F652
Hauptverfasser: Ko, Benjamin, Mistry, Abinash C, Hanson, Lauren, Mallick, Rickta, Wynne, Brandi M, Thai, Tiffany L, Bailey, James L, Klein, Janet D, Hoover, Robert S
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container_end_page F652
container_issue 5
container_start_page F645
container_title American journal of physiology. Renal physiology
container_volume 305
creator Ko, Benjamin
Mistry, Abinash C
Hanson, Lauren
Mallick, Rickta
Wynne, Brandi M
Thai, Tiffany L
Bailey, James L
Klein, Janet D
Hoover, Robert S
description 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.
doi_str_mv 10.1152/ajprenal.00053.2013
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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.</description><identifier>ISSN: 1931-857X</identifier><identifier>EISSN: 1522-1466</identifier><identifier>DOI: 10.1152/ajprenal.00053.2013</identifier><identifier>PMID: 23739593</identifier><language>eng</language><publisher>United States: American Physiological Society</publisher><subject>Adrenalectomy ; Aldosterone - pharmacology ; Animals ; Cells, Cultured ; Hormones ; Hypertension ; Immediate-Early Proteins - drug effects ; Immediate-Early Proteins - metabolism ; Kinases ; Male ; Mice ; Phosphorylation ; Phosphorylation - drug effects ; Protein-Serine-Threonine Kinases - drug effects ; Protein-Serine-Threonine Kinases - metabolism ; Protein-Serine-Threonine Kinases - physiology ; Rats ; Rats, Sprague-Dawley ; Receptors, Mineralocorticoid - drug effects ; Sodium ; Sodium Chloride Symporters - drug effects ; Sodium Chloride Symporters - physiology ; Solute Carrier Family 12, Member 3 - drug effects ; Steroids</subject><ispartof>American journal of physiology. 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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.</abstract><cop>United States</cop><pub>American Physiological Society</pub><pmid>23739593</pmid><doi>10.1152/ajprenal.00053.2013</doi><oa>free_for_read</oa></addata></record>
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source MEDLINE; American Physiological Society; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection
subjects Adrenalectomy
Aldosterone - pharmacology
Animals
Cells, Cultured
Hormones
Hypertension
Immediate-Early Proteins - drug effects
Immediate-Early Proteins - metabolism
Kinases
Male
Mice
Phosphorylation
Phosphorylation - drug effects
Protein-Serine-Threonine Kinases - drug effects
Protein-Serine-Threonine Kinases - metabolism
Protein-Serine-Threonine Kinases - physiology
Rats
Rats, Sprague-Dawley
Receptors, Mineralocorticoid - drug effects
Sodium
Sodium Chloride Symporters - drug effects
Sodium Chloride Symporters - physiology
Solute Carrier Family 12, Member 3 - drug effects
Steroids
title Aldosterone acutely stimulates NCC activity via a SPAK-mediated pathway
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