title: Aldosterone does not require angiotensin II to activate NCC through a WNK4-SPAK-dependent pathway.
abstract: We and others have recently shown that angiotensin II can activate the sodium chloride cotransporter (NCC) through a WNK4-SPAK-dependent pathway. Because WNK4 was previously shown to be a negative regulator of NCC, it has been postulated that angiotensin II converts WNK4 to a positive regulator. Here, we ask whether aldosterone requires angiotensin II to activate NCC and if their effects are additive. To do so, we infused vehicle or aldosterone in adrenalectomized rats that also received the angiotensin receptor blocker losartan. In the presence of losartan, aldosterone was still capable of increasing total and phosphorylated NCC twofold to threefold. The kinases WNK4 and SPAK also increased with aldosterone and losartan. A dose-dependent relationship between aldosterone and NCC, SPAK, and WNK4 was identified, suggesting that these are aldosterone-sensitive proteins. As more functional evidence of increased NCC activity, we showed that rats receiving aldosterone and losartan had a significantly greater natriuretic response to hydrochlorothiazide than rats receiving losartan only. To study whether angiotensin II could have an additive effect, rats receiving aldosterone with losartan were compared with rats receiving aldosterone only. Rats receiving aldosterone only retained more sodium and had twofold to fourfold increase in phosphorylated NCC. Together, our results demonstrate that aldosterone does not require angiotensin II to activate NCC and that WNK4 appears to act as a positive regulator in this pathway. The additive effect of angiotensin II may favor electroneutral sodium reabsorption during hypovolemia and may contribute to hypertension in diseases with an activated renin-angiotensin-aldosterone system.
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, PO Box 2040, Room D-405, 3000 CA, Rotterdam, The Netherlands.
authors.forename: Nils
authors.initials: N
authors.lastname: van der Lubbe
authors.forename: Christina H
authors.initials: CH
authors.lastname: Lim
authors.forename: Marcel E
authors.initials: ME
authors.lastname: Meima
authors.forename: Richard
authors.initials: R
authors.lastname: van Veghel
authors.forename: Lena Lindtoft
authors.initials: LL
authors.lastname: Rosenbaek
authors.forename: Kerim
authors.initials: K
authors.lastname: Mutig
authors.forename: Alexander H J
authors.initials: AH
authors.lastname: Danser
authors.forename: Robert A
authors.initials: RA
authors.lastname: Fenton
authors.forename: Robert
authors.initials: R
authors.lastname: Zietse
authors.forename: Ewout J
authors.initials: EJ
authors.lastname: Hoorn
mesh_terms: D000315:Adrenalectomy; D000450:Aldosterone / Q000494:pharmacology / Q000502:physiology*; D000584:Amiloride / Q000494:pharmacology; D000804:Angiotensin II / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D004232:Diuretics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006852:Hydrochlorothiazide / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D019808:Losartan / Q000494:pharmacology; D023421:Models, Animal; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D049992:Sodium Chloride Symporters / Q000502:physiology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D004232:Diuretics; D049992:Sodium Chloride Symporters; D006852:Hydrochlorothiazide; D000804:Angiotensin II; D000450:Aldosterone; D000584:Amiloride; C499025:Wnk4 protein, rat; C116037:PAS domain kinases; D017346:Protein Serine-Threonine Kinases; D019808:Losartan