Disruption of the with no lysine kinase-STE20-proline alanine-rich kinase pathway reduces the hypertension induced by angiotensin II

Luz Graciela Cervantes-Perez, Maria Castaneda-Bueno, Jose V. Jimenez, Norma Vazquez, Lorena Rojas-Vega, Dario Alessi, Norma A. Bobadilla, Gerardo Gamba (Lead / Corresponding author)

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Objective: The hypertensive effect of angiotensin II (AngII), a peptide hormone, is dependent on its intrarenal actions and the activation of the renal Na–Cl cotransporter (NCC), by AngII requires integrity of the with no lysine kinase/STE20-proline alanine rich kinase (WNK/SPAK) signaling pathway. Here, were analyzed if the integrity of the WNK/SPAK pathway is required for AngII infusion to induce arterial hypertension.

Methods: We tested the effect of AngII or aldosterone administration on the blood pressure and on pNCC/NCC ratio in SPAKT243A/243A knock-in mice in which the kinase and thus NCC cannot be activated by WNK kinases. AngII or aldosterone was infused at 1440 or 700 mg/kg/d, respectively, for 14 days using osmotic minipumps. The aldosterone-treated mice were exposed to NaCl drinking water (1%) during the hormone administration. The arterial blood pressure was assessed using radiotelemetry.

Results: We observed that in the SPAK knock-in mice, the AngII-induced hypertensive effect was significantly reduced and associated with an absence of AngII-induced NCC
phosphorylation. In contrast, the hypertensive effect of aldosterone was enhanced and was related with an increased response to amiloride, but not to thiazide-type
diuretics, without a significant increase in NCC phosphorylation.

Conclusion: Our data suggest that AngII-induced hypertension requires, at least partly, NCC activation via the WNK/SPAK signaling pathway, whereas aldosterone-induced hypertension depends on ENaC activation in a WNK/SPAKindependent manner. SPAK knock-in mice emerge as a useful model to distinguish between the effects of AngII and aldosterone on distal nephrons.
Original languageEnglish
Pages (from-to)361-367
Number of pages7
JournalJournal of Hypertension
Issue number2
Early online date14 Sept 2017
Publication statusPublished - 1 Feb 2018


  • aldosterone
  • distal convoluted tubule
  • salt transport
  • thiazide
  • with no lysine kinase 4

ASJC Scopus subject areas

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine


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