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

• Published in: Journal of hypertension Vol. 36; no. 2; p. 361
• Main Authors: Cervantes-Perez, Luz G, Castaneda-Bueno, Maria, Jimenez, Jose V, Vazquez, Norma, Rojas-Vega, Lorena, Alessi, Dario R, Bobadilla, Norma A, Gamba, Gerardo
• Format: Journal Article
• Language: English
• Published: England 01.02.2018
• Subjects: Aldosterone - pharmacology; Amiloride - pharmacology; Angiotensin II - pharmacology; Animals; Blood Pressure - drug effects; Diuretics - pharmacology; Epithelial Sodium Channels - metabolism; Gene Knock-In Techniques; Hypertension - chemically induced; Hypertension - metabolism; Male; Mice; Phosphorylation; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Signal Transduction; Sodium Chloride Symporter Inhibitors - pharmacology; Solute Carrier Family 12, Member 3 - metabolism
• ISSN: 1473-5598
• DOI: 10.1097/HJH.0000000000001554

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, we analyzed if the integrity of the WNK/SPAK pathway is required for AngII infusion to induce arterial hypertension. We tested the effect of AngII or aldosterone administration on the blood pressure and on pNCC/NCC ratio in SPAK 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 μg/kg per day, 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. 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. 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 epithelial sodium channel activation in a WNK/SPAK-independent manner. SPAK knock-in mice emerge as a useful model to distinguish between the effects of AngII and aldosterone on distal nephrons.