Disruption of the with no lysine kinase STE20-proline alanine-rich kinase pathway reduces the hypertension induced by angiotensin II
Por:
Cervantes-Perez L.G., Castaneda-Bueno M., Jimenez J.V., Vazquez N., Rojas-Vega L., Alessi D.R., Bobadilla N.A., Gamba G.
Publicada:
1 feb 2018
Resumen:
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 700mg/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.
Filiaciones:
Cervantes-Perez L.G.:
Department of Pharmacology, Instituto Nacional de Cardiología Ignacio Chávez, Mexico
Castaneda-Bueno M.:
Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga No. 15, Mexico City, Mexico
Jimenez J.V.:
Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga No. 15, Mexico City, Mexico
Vazquez N.:
Molecular Physiology Unit, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico
Rojas-Vega L.:
Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga No. 15, Mexico City, Mexico
Alessi D.R.:
MRC Phosphorylation and Ubiquytilation Unit, Dundee University, Dundee, United Kingdom
Bobadilla N.A.:
Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga No. 15, Mexico City, Mexico
Molecular Physiology Unit, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico
Gamba G.:
Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga No. 15, Mexico City, Mexico
Molecular Physiology Unit, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico
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