Elucidating the Contribution of OVLT Glutamatergic Neurons to Mineralocorticoid Hypertension in TASK −/− Mice
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Background
Aldosterone overactivity intensifies central sodium sensitivity and sympathetic output, driving salt-sensitive hypertension, but specific mechanisms remain incompletely defined. Herein, we aimed to explore the role of organum vasculosum of the lamina terminalis glutamatergic neurons (OVLT Glut ) and their hyperexcitability mechanisms in hyperaldosteronism-associated hypertension.
Methods
Adult age matched male TASK −/− mice (primary aldosteronism model) and wild-type controls (TASK +/+ ) mice were used. Neuronal excitability was assessed via patch-clamp techniques. Arterial blood pressure (BP) monitored via telemetry or carotid catheterization. Chronic drug delivery used minipumps. RNA-seq/qPCR profiled gene expression, and intracerebroventricular hypertonic saline tested sodium sensitivity.
Results
In TASK −/− mice, heightened OVLT Glut activity increased sympathetic outflow and hypertension, mitigated by OVLT Glut neuron ablation. Optogenetic activation of these neurons or their paraventricular nucleus (PVN) / rostral ventrolateral medulla (RVLM) projections acutely elevated BP, with ablation reducing BP selectively in TASK −/− mice. Aldosterone dependence of OVLT Glut -PVN/RVLM neuron hyperactivity was evident in both TASK −/− mice and TASK +/+ mice with chronic aldosterone infusion. Aldosterone chronic infusion enhanced central sodium pressor effects, that were nullified by OVLT Glut -PVN/RVLM neuron lesioning. RNA-seq indicated that aldosterone-induced ion channel expression spectrum changes, including potassium channels and the epithelial sodium channel, underlie the neuronal hyperexcitability.
Conclusion
Overactivation of OVLT Glut neurons contributes to hypertension in TASK −/− mice through regulation of OVLT Glut -PVN/RVLM circuits. The hyperexcitability of these neurons, possibly due to aldosterone-induced changes in ion channel expression spectrum, contribute to hypertension by amplifying central sodium sensitivity.
