{"title":"抗原攻击小鼠气道中肾素-血管紧张素系统基因表达的改变:ACE2下调和血管紧张素1-7的意外增加","authors":"Yoshihiko Chiba , Mana Ito , Yusuke Ando , Chihiro Ueda , Michio Yamashita , Wataru Suto , Shota Ishizaka , Ai Torizuka , Chie Watanabe , Fumiko Takenoya , Motohiko Hanazaki , Hiroyasu Sakai","doi":"10.1016/j.resp.2023.104137","DOIUrl":null,"url":null,"abstract":"<div><h3>Objective</h3><p>Evidence suggest that the renin-angiotensin system (RAS) is activated in people with asthma, although its pathophysiological role is unclear. Angiotensin-converting enzyme 2 (ACE2) is the major enzyme that converts angiotensin II to angiotensin 1–7 (Ang-1–7), and is also known as a receptor of SARS-CoV-2. The current study was conducted to identify the change in RAS-related gene expression in airways of a murine asthma model.</p></div><div><h3>Methods</h3><p>The ovalbumin (OA)-sensitized mice were repeatedly challenged with aerosolized OA to induce asthmatic reaction. Twenty-four hours after the last antigen challenge, the main bronchial smooth muscle (BSM) tissues were isolated.</p></div><div><h3>Results</h3><p>The KEGG pathway analysis of differentially expressed genes in our published microarray data revealed a significant change in the RAS pathway in the antigen-challenged mice. Quantitative RT-PCR analyses showed significant increases in the angiotensin II-generating enzymes (<em>Klk1</em>, <em>Klk1b3</em> and <em>Klk1b8</em>) and a significant decrease in <em>Ace2</em>. Surprisingly, ELISA analyses revealed a significant increase in Ang-1–7 levels in bronchoalveolar lavage (BAL) fluids of the antigen-challenged animals, while no significant change in angiotensin II was observed. Application of Ang-1–7 to the isolated BSMs had no effect on their isometrical tension.</p></div><div><h3>Conclusion</h3><p>The expression of <em>Ace2</em> was downregulated in the BSMs of OA-challenged mice, while <em>Klk1</em>, <em>Klk1b3</em> and <em>Klk1b8</em> were upregulated. Despite the downregulation of ACE2, the level of its enzymatic product, Ang-1–7, was increased in the inflamed airways, suggesting the existence of an unknown ACE2-independent pathway for Ang-1–7 production. The functional role of Ang-1–7 in the airways remains unclear.</p></div>","PeriodicalId":20961,"journal":{"name":"Respiratory Physiology & Neurobiology","volume":null,"pages":null},"PeriodicalIF":1.9000,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Altered renin-angiotensin system gene expression in airways of antigen-challenged mice: ACE2 downregulation and unexpected increase in angiotensin 1–7\",\"authors\":\"Yoshihiko Chiba , Mana Ito , Yusuke Ando , Chihiro Ueda , Michio Yamashita , Wataru Suto , Shota Ishizaka , Ai Torizuka , Chie Watanabe , Fumiko Takenoya , Motohiko Hanazaki , Hiroyasu Sakai\",\"doi\":\"10.1016/j.resp.2023.104137\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Objective</h3><p>Evidence suggest that the renin-angiotensin system (RAS) is activated in people with asthma, although its pathophysiological role is unclear. Angiotensin-converting enzyme 2 (ACE2) is the major enzyme that converts angiotensin II to angiotensin 1–7 (Ang-1–7), and is also known as a receptor of SARS-CoV-2. The current study was conducted to identify the change in RAS-related gene expression in airways of a murine asthma model.</p></div><div><h3>Methods</h3><p>The ovalbumin (OA)-sensitized mice were repeatedly challenged with aerosolized OA to induce asthmatic reaction. Twenty-four hours after the last antigen challenge, the main bronchial smooth muscle (BSM) tissues were isolated.</p></div><div><h3>Results</h3><p>The KEGG pathway analysis of differentially expressed genes in our published microarray data revealed a significant change in the RAS pathway in the antigen-challenged mice. Quantitative RT-PCR analyses showed significant increases in the angiotensin II-generating enzymes (<em>Klk1</em>, <em>Klk1b3</em> and <em>Klk1b8</em>) and a significant decrease in <em>Ace2</em>. Surprisingly, ELISA analyses revealed a significant increase in Ang-1–7 levels in bronchoalveolar lavage (BAL) fluids of the antigen-challenged animals, while no significant change in angiotensin II was observed. Application of Ang-1–7 to the isolated BSMs had no effect on their isometrical tension.</p></div><div><h3>Conclusion</h3><p>The expression of <em>Ace2</em> was downregulated in the BSMs of OA-challenged mice, while <em>Klk1</em>, <em>Klk1b3</em> and <em>Klk1b8</em> were upregulated. Despite the downregulation of ACE2, the level of its enzymatic product, Ang-1–7, was increased in the inflamed airways, suggesting the existence of an unknown ACE2-independent pathway for Ang-1–7 production. The functional role of Ang-1–7 in the airways remains unclear.</p></div>\",\"PeriodicalId\":20961,\"journal\":{\"name\":\"Respiratory Physiology & Neurobiology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":1.9000,\"publicationDate\":\"2023-10-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Respiratory Physiology & Neurobiology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1569904823001258\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"PHYSIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Respiratory Physiology & Neurobiology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1569904823001258","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"PHYSIOLOGY","Score":null,"Total":0}
Altered renin-angiotensin system gene expression in airways of antigen-challenged mice: ACE2 downregulation and unexpected increase in angiotensin 1–7
Objective
Evidence suggest that the renin-angiotensin system (RAS) is activated in people with asthma, although its pathophysiological role is unclear. Angiotensin-converting enzyme 2 (ACE2) is the major enzyme that converts angiotensin II to angiotensin 1–7 (Ang-1–7), and is also known as a receptor of SARS-CoV-2. The current study was conducted to identify the change in RAS-related gene expression in airways of a murine asthma model.
Methods
The ovalbumin (OA)-sensitized mice were repeatedly challenged with aerosolized OA to induce asthmatic reaction. Twenty-four hours after the last antigen challenge, the main bronchial smooth muscle (BSM) tissues were isolated.
Results
The KEGG pathway analysis of differentially expressed genes in our published microarray data revealed a significant change in the RAS pathway in the antigen-challenged mice. Quantitative RT-PCR analyses showed significant increases in the angiotensin II-generating enzymes (Klk1, Klk1b3 and Klk1b8) and a significant decrease in Ace2. Surprisingly, ELISA analyses revealed a significant increase in Ang-1–7 levels in bronchoalveolar lavage (BAL) fluids of the antigen-challenged animals, while no significant change in angiotensin II was observed. Application of Ang-1–7 to the isolated BSMs had no effect on their isometrical tension.
Conclusion
The expression of Ace2 was downregulated in the BSMs of OA-challenged mice, while Klk1, Klk1b3 and Klk1b8 were upregulated. Despite the downregulation of ACE2, the level of its enzymatic product, Ang-1–7, was increased in the inflamed airways, suggesting the existence of an unknown ACE2-independent pathway for Ang-1–7 production. The functional role of Ang-1–7 in the airways remains unclear.
期刊介绍:
Respiratory Physiology & Neurobiology (RESPNB) publishes original articles and invited reviews concerning physiology and pathophysiology of respiration in its broadest sense.
Although a special focus is on topics in neurobiology, high quality papers in respiratory molecular and cellular biology are also welcome, as are high-quality papers in traditional areas, such as:
-Mechanics of breathing-
Gas exchange and acid-base balance-
Respiration at rest and exercise-
Respiration in unusual conditions, like high or low pressure or changes of temperature, low ambient oxygen-
Embryonic and adult respiration-
Comparative respiratory physiology.
Papers on clinical aspects, original methods, as well as theoretical papers are also considered as long as they foster the understanding of respiratory physiology and pathophysiology.