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. 2025 Feb;82(2):282-292.
doi: 10.1161/HYPERTENSIONAHA.124.23740. Epub 2024 Dec 2.

Definitive Evidence for the Identification and Function of Renin-Expressing Cholinergic Neurons in the Nucleus Ambiguus

Éva M Fekete  1 , Javier Gomez  1 , Mina Ghobrial  1 , Kathren Kaminski  1 , Patricia C Muskus  1 , Carie R Boychuk  2 , Ana Hantke Guixa  1 , Ibrahim Vazirabad  1 , Michelle Xie  1 , Azeez Ganiyu  1 , Daria Golosova  1 , Natalia M Mathieu  1 , Yoko B Wang  2 , Ko-Ting Lu  1 , Kelsey K Wackman  1 , Daniel T Brozoski  1 , Gary C Mouradian  1 , Matthew R Hodges  1 , Jeffrey L Segar  1   3   4 , Justin L Grobe  1   3   5   6   7 , Curt D Sigmund  1   3   5 , Pablo Nakagawa  1   3   5
Affiliations

Definitive Evidence for the Identification and Function of Renin-Expressing Cholinergic Neurons in the Nucleus Ambiguus

Éva M Fekete et al. Hypertension. 2025 Feb.

Abstract

Background: The importance of the brain renin-angiotensin system in cardiovascular function is well accepted. However, not knowing the precise source of renin in the brain has been a limitation toward a complete understanding of how the brain renin-angiotensin system operates.

Methods: Highly sensitive in situ hybridization techniques and conditional knockout mice were used to address the location and function of renin in the brainstem.

Results: We identified novel renin-expressing cholinergic neurons in the nucleus ambiguus (NuAm), a major vagal cardioinhibitory center in the brainstem. The expression of renin-angiotensin system genes was relatively abundant in the NuAm, implying that angiotensin II might mediate an important regulatory role in this nucleus and other regions with neural connectivity to the NuAm. Then, we generated conditional knockout mice lacking the classical renin isoform (Ren-aChAT-KO), specifically in cholinergic neurons. Ablation of Ren-a in cholinergic neurons abrogated renin expression in the NuAm. Moreover, studies using radiotelemetry, heart rate variability analyses, and pharmacological approaches revealed that the parasympathetic nervous system is depressed in Ren-aChAT-KO males while augmented in the Ren-aChAT-KO females. Subsequently, transcriptomic approaches were used to infer putative genes and signaling pathways regulated by renin within the NuAm.

Conclusions: This study revealed that renin in cholinergic neurons plays a fundamental role in preserving autonomic balance and cardiovascular homeostasis in a sex-dependent manner. These findings define the NuAm as an endogenous, local source of renin with biological function and serve as conclusive evidence for the presence and functionality of the brain renin-angiotensin system.

Keywords: autonomic nervous system; brain stem; heart rate; medulla oblongata; parasympathetic nervous system; renin-angiotensin system.

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Conflict of interest statement

None.

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