Angiotensin II Infusion Results in Both Hypertension and Increased AMPA GluA1 Signaling in Hypothalamic Paraventricular Nucleus of Male but not Female Mice.

The hypothalamic paraventricular nucleus (PVN) plays a key role in hypertension, however the signaling pathways that contribute to the adaptability of the PVN during hypertension are uncertain. We present evidence that signaling at the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) GluA1 receptor subunit contributes to increased blood pressure in a model of neurogenic hypertension induced by 14-day slow-pressor angiotensin II (AngII) infusion in male mice. It was found that AngII hypertension was associated with an increase in plasma membrane affiliation of GluA1, but decreased GluA2, in dendritic profiles of PVN neurons. The increased plasma membrane GluA1 was paralleled by the results of whole-cell current clamping experiments, which showed heightened AMPA currents in PVN neurons from AngII-infused male mice. The inhibition of heightened AMPA currents was blocked by 1-Naphthyl acetyl spermine trihydrochloride, pointing to the involvement of GluA2-lacking GluA1 receptors in the elevated AMPA signaling in PVN neurons. A further functional role for GluA1 signaling in the PVN was demonstrated by the attenuated hypertensive response following silencing of GluA1 in the PVN of AngII-infused mice. In female mice, AngII-infusion did not impact blood pressure. In addition, AngII was not associated with alterations in transcription or plasma membrane localization of GluA1 in females. Posttranslational modifications that increase the plasma membrane localization of AMPA GluA1 and heighten the rapid signaling actions of glutamate in PVN neurons may serve as a molecular substrate underlying sex differences in hypertension.