Disruption of the WNK/SPAK pathway attenuates angiotensin II, but enhances aldosterone‐induced hypertension (1136.3)

Abstract

It is known that angiotensin II (AngII) hypertensive effect is dependent on the intrarenal actions of this peptide hormone. On the other hand, we have proposed that AngII effect on the renal NaCl cotransporter, NCC, requires integrity of the WNK/SPAK pathway. We thus tested the effect of AngII or aldosterone administration on blood pressure in SPAK knockin mice in which the T243A mutation prevents the WNK activation of SPAK and thus, NCC activation.AngII or aldosterone was infused at 1440μg/kg/d or 700μg/kg/d, respectively, in SPAK wild type and SPAKT243A knockin mice for 14 days by osmotic minipumps. Aldosterone treated mice were exposed to NaCl drinking water (1%) during the hormone administration. Arterial blood pressure was assessed by radiotelemetry. Electrolyte excretion after diuretic challenge and NCC protein expression and phosphorylation was assessed on day 14. Our results show that hypertensive effect of AngII was blunted by at least half in SPAK‐knockin mice, together with absence of AngII induced NCC phosphorylation. In contrast, the hypertensive effect of aldosterone was enhanced. In wild type mice blood pressure was not significantly modified during aldosterone administration, while in SPAK‐knockin mice hypertension was developed. Aldosterone treatment was associated with increased response to amiloride, but not to thiazide diuretics, and no increase in NCC phosphorylation was observed. Thus, our work suggest that AngII induced hypertension requires, at least in part, NCC activation via WNK/SPAK signaling pathway, while aldosterone induced hypertension depends on ENaC activation that is WNK/SPAK independent. The SPAK‐KI mice emerges as a useful model to distinguish between the AngII vs aldosterone effects on distal nephron.