Definitive Evidence for the Identification and Function of Renin-Expressing Cholinergic Neurons in the Nucleus Ambiguus. Hypertension 2025 Feb;82(2):282-292
Date
12/02/2024Pubmed ID
39618396Pubmed Central ID
PMC11735315DOI
10.1161/HYPERTENSIONAHA.124.23740Scopus ID
2-s2.0-85210962734 (requires institutional sign-in at Scopus site) 3 CitationsAbstract
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.
Author List
Fekete ÉM, Gomez J, Ghobrial M, Kaminski K, Muskus PC, Boychuk CR, Hantke Guixa A, Vazirabad I, Xie M, Ganiyu A, Golosova D, Mathieu NM, Wang YB, Lu KT, Wackman KK, Brozoski DT, Mouradian GC, Hodges MR, Segar JL, Grobe JL, Sigmund CD, Nakagawa PAuthors
Justin L. Grobe PhD Professor in the Physiology department at Medical College of WisconsinMatthew R. Hodges PhD Professor in the Physiology department at Medical College of Wisconsin
Pablo Nakagawa PhD Assistant Professor in the Physiology department at Medical College of Wisconsin
Jeffrey L. Segar MD Professor in the Pediatrics department at Medical College of Wisconsin
Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of Wisconsin
Ibrahim Y. Vazirabad Bioinformatics Analyst III in the Physiology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsCholinergic Neurons
Female
Heart Rate
Male
Medulla Oblongata
Mice
Mice, Knockout
Parasympathetic Nervous System
Renin
Renin-Angiotensin System
