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, Sigmund Curt D, Nakagawa Pablo
Department of Physiology (E.M.F., J.G., M.G., K.K., P.C.M., A.H.G., I.V., M.X., A.G., D.G., N.M.M., K.-T.L., K.K.W., D.T.B., G.C.M., M.R.H., J.L.S., J.L.G., C.D.S., P.N.), Medical College of Wisconsin, Milwaukee.
Department of Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia (C.R.B., Y.B.W.).
Hypertension. 2025 Feb;82(2):282-292. doi: 10.1161/HYPERTENSIONAHA.124.23740. Epub 2024 Dec 2.
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.
Highly sensitive in situ hybridization techniques and conditional knockout mice were used to address the location and function of renin in the brainstem.
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), 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 males while augmented in the Ren-a females. Subsequently, transcriptomic approaches were used to infer putative genes and signaling pathways regulated by renin within the NuAm.
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.
脑肾素 - 血管紧张素系统在心血管功能中的重要性已得到广泛认可。然而，不清楚脑中肾素的确切来源一直是全面理解脑肾素 - 血管紧张素系统如何运作的一个限制因素。
采用高度敏感的原位杂交技术和条件性敲除小鼠来研究脑干中肾素的定位和功能。
我们在疑核（NuAm）中鉴定出了新的表达肾素的胆碱能神经元，疑核是脑干中主要的迷走神经心抑制中心。肾素 - 血管紧张素系统基因在疑核中的表达相对丰富，这意味着血管紧张素II可能在该核以及与疑核有神经连接的其他区域介导重要的调节作用。然后，我们构建了特异性在胆碱能神经元中缺乏经典肾素异构体（Ren - a）的条件性敲除小鼠。胆碱能神经元中Ren - a的缺失消除了疑核中的肾素表达。此外，使用无线电遥测、心率变异性分析和药理学方法的研究表明，Ren - a雄性小鼠的副交感神经系统受到抑制，而Ren - a雌性小鼠的副交感神经系统则增强。随后，采用转录组学方法推断疑核内受肾素调节的假定基因和信号通路。
本研究表明，胆碱能神经元中的肾素在以性别依赖的方式维持自主平衡和心血管稳态方面发挥着重要作用。这些发现将疑核定义为具有生物学功能的内源性肾素局部来源，并为脑肾素 - 血管紧张素系统的存在和功能提供了确凿证据。
