Peltekian Lila, Gasparini Silvia, Fazan Frederico S, Karthik Samyukta, Iverson Gabrielle, Resch Jon M, Geerling Joel C
Department of Neurology, University of Iowa, Iowa City, IA, USA.
Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA.
J Physiol. 2023 Aug;601(16):3499-3532. doi: 10.1113/JP283169. Epub 2023 Jun 27.
In addition to its renal and cardiovascular functions, angiotensin signalling is thought to be responsible for the increases in salt and water intake caused by hypovolaemia. However, it remains unclear whether these behaviours require angiotensin production in the brain or liver. Here, we use in situ hybridization to identify tissue-specific expression of the genes required for producing angiotensin peptides, and then use conditional genetic deletion of the angiotensinogen gene (Agt) to test whether production in the brain or liver is necessary for sodium appetite and thirst. In the mouse brain, we identified expression of Agt (the precursor for all angiotensin peptides) in a large subset of astrocytes. We also identified Ren1 and Ace (encoding enzymes required to produce angiotensin II) expression in the choroid plexus, and Ren1 expression in neurons within the nucleus ambiguus compact formation. In the liver, we confirmed that Agt is widely expressed in hepatocytes. We next tested whether thirst and sodium appetite require angiotensinogen production in astrocytes or hepatocytes. Despite virtually eliminating expression in the brain, deleting astrocytic Agt did not reduce thirst or sodium appetite. Despite markedly reducing angiotensinogen in the blood, eliminating Agt from hepatocytes did not reduce thirst or sodium appetite, and in fact, these mice consumed the largest amounts of salt and water after sodium deprivation. Deleting Agt from both astrocytes and hepatocytes also did not prevent thirst or sodium appetite. Our findings suggest that angiotensin signalling is not required for sodium appetite or thirst and highlight the need to identify alternative signalling mechanisms. KEY POINTS: Angiotensin signalling is thought to be responsible for the increased thirst and sodium appetite caused by hypovolaemia, producing elevated water and sodium intake. Specific cells in separate brain regions express the three genes needed to produce angiotensin peptides, but brain-specific deletion of the angiotensinogen gene (Agt), which encodes the lone precursor for all angiotensin peptides, did not reduce thirst or sodium appetite. Double-deletion of Agt from brain and liver also did not reduce thirst or sodium appetite. Liver-specific deletion of Agt reduced circulating angiotensinogen levels without reducing thirst or sodium appetite. Instead, these angiotensin-deficient mice exhibited an enhanced sodium appetite. Because the physiological mechanisms controlling thirst and sodium appetite continued functioning without angiotensin production in the brain and liver, understanding these mechanisms requires a renewed search for the hypovolaemic signals necessary for activating each behaviour.
除了其肾脏和心血管功能外，血管紧张素信号传导被认为是低血容量引起的盐和水摄入量增加的原因。然而，目前尚不清楚这些行为是否需要大脑或肝脏产生血管紧张素。在这里，我们使用原位杂交来鉴定产生血管紧张素肽所需基因的组织特异性表达，然后使用血管紧张素原基因（Agt）的条件性基因缺失来测试大脑或肝脏中的产生对于钠食欲和口渴是否必要。在小鼠大脑中，我们在大量星形胶质细胞亚群中鉴定出Agt（所有血管紧张素肽的前体）的表达。我们还在脉络丛中鉴定出Ren1和Ace（编码产生血管紧张素II所需的酶）的表达，以及在疑核紧密形成内的神经元中鉴定出Ren1的表达。在肝脏中，我们证实Agt在肝细胞中广泛表达。接下来，我们测试了口渴和钠食欲是否需要星形胶质细胞或肝细胞产生血管紧张素原。尽管几乎消除了大脑中的表达，但删除星形胶质细胞Agt并没有降低口渴或钠食欲。尽管显著降低了血液中的血管紧张素原，但从肝细胞中消除Agt并没有降低口渴或钠食欲，事实上，这些小鼠在缺钠后消耗了最多的盐和水。从星形胶质细胞和肝细胞中删除Agt也不能阻止口渴或钠食欲。我们的研究结果表明，血管紧张素信号传导对于钠食欲或口渴不是必需的，并强调了识别替代信号传导机制的必要性。要点：血管紧张素信号传导被认为是低血容量引起的口渴增加和钠食欲增加的原因，导致水和钠摄入量升高。不同脑区的特定细胞表达产生血管紧张素肽所需的三个基因，但编码所有血管紧张素肽唯一前体的血管紧张素原基因（Agt）的脑特异性缺失并没有降低口渴或钠食欲。从大脑和肝脏中双重删除Agt也没有降低口渴或钠食欲。肝脏特异性删除Agt降低了循环血管紧张素原水平，但没有降低口渴或钠食欲。相反，这些血管紧张素缺乏的小鼠表现出增强的钠食欲。由于在大脑和肝脏中没有血管紧张素产生的情况下，控制口渴和钠食欲的生理机制仍在继续发挥作用，因此理解这些机制需要重新寻找激活每种行为所需的低血容量信号。
