Elucidating the Contribution of OVLT Glutamatergic Neurons to Mineralocorticoid Hypertension in TASK−/−Mice

  1. Luo Shi
  2. Kun Liu
  3. Ke Zhao
  4. Wei He
  5. Yongqiang Chen
  6. Xue Zhao
  7. Yanxuan Wei
  8. Jinting Chen
  9. Sheng Wang
  10. Fang Yuan
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Abstract

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 (OVLTGlut) 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 OVLTGlutactivity increased sympathetic outflow and hypertension, mitigated by OVLTGlutneuron 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 OVLTGlut-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 OVLTGlut-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 OVLTGlutneurons contributes to hypertension in TASK−/−mice through regulation of OVLTGlut-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.

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