Disruption of the with no lysine kinase–STE20-proline alanine-rich kinase pathway reduces the hypertension induced by angiotensin II. Issue 2 (February 2018)

• Record Type: Journal Article
• Authors: Cervantes-Perez, Luz G.; Castaneda-Bueno, Maria; Jimenez, Jose V.; Vazquez, Norma; Rojas-Vega, Lorena; Alessi, Dario R.; Bobadilla, Norma A.; Gamba, Gerardo
• Is Part Of: Journal of hypertension. Volume 36:Issue 2(2018:Feb.)
• Publication Date: 2018-02
• Subjects: aldosterone -- distal convoluted tubule -- salt transport -- thiazide -- with no lysine kinase 4; Hypertension -- Periodicals; Hypertension -- Periodicals; 616.132005
• DOI: 10.1097/HJH.0000000000001554
• Languages: English
• ISSNs: 1473-5598

Abstract

Abstract : 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, we 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 SPAK T243A/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 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. 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 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. Abstract : Supplemental Digital Content is available in the text