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

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Title: Definitive Evidence for the Identification and Function of Renin-Expressing Cholinergic Neurons in the Nucleus Ambiguus.
Authors: Fekete, Éva M., Gomez, Javier, Ghobrial, Mina, Kaminski, Kathren, Muskus, Patricia C., Boychuk, Carie R., Hantke Guixa, Ana, Vazirabad, Ibrahim, Xie, Michelle, Ganiyu, Azeez, Golosova, Daria, Mathieu, Natalia M., Wang, Yoko B., Lu, Ko-Ting, Wackman, Kelsey K., Brozoski, Daniel T., Mouradian, Gary C., Hodges, Matthew R., Segar, Jeffrey L., Grobe, Justin L.
Source: Hypertension (0194911X); Feb2025, Vol. 82 Issue 2, p282-292, 11p
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. [ABSTRACT FROM AUTHOR]
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  Data: Definitive Evidence for the Identification and Function of Renin-Expressing Cholinergic Neurons in the Nucleus Ambiguus.
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  Data: <searchLink fieldCode="AR" term="%22Fekete%2C+Éva+M%2E%22">Fekete, Éva M.</searchLink><br /><searchLink fieldCode="AR" term="%22Gomez%2C+Javier%22">Gomez, Javier</searchLink><br /><searchLink fieldCode="AR" term="%22Ghobrial%2C+Mina%22">Ghobrial, Mina</searchLink><br /><searchLink fieldCode="AR" term="%22Kaminski%2C+Kathren%22">Kaminski, Kathren</searchLink><br /><searchLink fieldCode="AR" term="%22Muskus%2C+Patricia+C%2E%22">Muskus, Patricia C.</searchLink><br /><searchLink fieldCode="AR" term="%22Boychuk%2C+Carie+R%2E%22">Boychuk, Carie R.</searchLink><br /><searchLink fieldCode="AR" term="%22Hantke+Guixa%2C+Ana%22">Hantke Guixa, Ana</searchLink><br /><searchLink fieldCode="AR" term="%22Vazirabad%2C+Ibrahim%22">Vazirabad, Ibrahim</searchLink><br /><searchLink fieldCode="AR" term="%22Xie%2C+Michelle%22">Xie, Michelle</searchLink><br /><searchLink fieldCode="AR" term="%22Ganiyu%2C+Azeez%22">Ganiyu, Azeez</searchLink><br /><searchLink fieldCode="AR" term="%22Golosova%2C+Daria%22">Golosova, Daria</searchLink><br /><searchLink fieldCode="AR" term="%22Mathieu%2C+Natalia+M%2E%22">Mathieu, Natalia M.</searchLink><br /><searchLink fieldCode="AR" term="%22Wang%2C+Yoko+B%2E%22">Wang, Yoko B.</searchLink><br /><searchLink fieldCode="AR" term="%22Lu%2C+Ko-Ting%22">Lu, Ko-Ting</searchLink><br /><searchLink fieldCode="AR" term="%22Wackman%2C+Kelsey+K%2E%22">Wackman, Kelsey K.</searchLink><br /><searchLink fieldCode="AR" term="%22Brozoski%2C+Daniel+T%2E%22">Brozoski, Daniel T.</searchLink><br /><searchLink fieldCode="AR" term="%22Mouradian%2C+Gary+C%2E%22">Mouradian, Gary C.</searchLink><br /><searchLink fieldCode="AR" term="%22Hodges%2C+Matthew+R%2E%22">Hodges, Matthew R.</searchLink><br /><searchLink fieldCode="AR" term="%22Segar%2C+Jeffrey+L%2E%22">Segar, Jeffrey L.</searchLink><br /><searchLink fieldCode="AR" term="%22Grobe%2C+Justin+L%2E%22">Grobe, Justin L.</searchLink>
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  Data: Hypertension (0194911X); Feb2025, Vol. 82 Issue 2, p282-292, 11p
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: 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-a<superscript>ChAT-KO</superscript>), 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-a<superscript>ChAT-KO</superscript> males while augmented in the Ren-a<superscript>ChAT-KO</superscript> 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. [ABSTRACT FROM AUTHOR]
– Name: Abstract
  Label:
  Group: Ab
  Data: <i>Copyright of Hypertension (0194911X) is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1161/HYPERTENSIONAHA.124.23740
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        Text: English
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              Text: Feb2025
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