Unlocking the protective potential of the angiotensin type 2 receptor (AT2R) in acute lung injury and age-related pulmonary dysfunction
Copyright © 2023 Elsevier Inc. All rights reserved..
Despite its known importance in the cardiovascular system, the specific role and impact of the angiotensin type 2 receptor (AT2R) in lung physiology and pathophysiology remain largely elusive. In this study, we highlight the distinct and specialized lung-specific roles of AT2R, primarily localized to an alveolar fibroblast subpopulation, in contrast to the angiotensin type 1 receptor (AT1R), which is almost exclusively expressed in lung pericytes. Evidence from our research demonstrates that the disruption of AT2R (AT2R-/y), is associated with a surge in oxidative stress and impaired lung permeability, which were further intensified by Hyperoxic Acute Lung Injury (HALI). With aging, AT2R-/y mice show an increase in oxidative stress, premature enlargement of airspaces, as well as increased mortality when exposed to hyperoxia as compared to age-matched WT mice. Our investigation into Losartan, an AT1R blocker, suggests that its primary HALI lung-protective effects are channeled through AT2R, as its protective benefits are absent in AT2R-/y mice. Importantly, a non-peptide AT2R agonist, Compound 21 (C21), successfully reverses lung oxidative stress and TGFβ activation in wild-type (WT) mice exposed to HALI. These findings suggest a possible paradigm shift in the therapeutic approach for lung injury and age-associated pulmonary dysfunction, from targeting AT1R with angiotensin receptor blockers (ARBs) towards boosting the protective function of AT2R.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:220 |
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| Enthalten in: |
Biochemical pharmacology - 220(2024) vom: 11. Feb., Seite 115978 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Abadir, Peter [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 29.01.2024 Date Revised 02.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bcp.2023.115978 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Copyright © 2023 Elsevier Inc. All rights reserved. | ||
| 520 | |a Despite its known importance in the cardiovascular system, the specific role and impact of the angiotensin type 2 receptor (AT2R) in lung physiology and pathophysiology remain largely elusive. In this study, we highlight the distinct and specialized lung-specific roles of AT2R, primarily localized to an alveolar fibroblast subpopulation, in contrast to the angiotensin type 1 receptor (AT1R), which is almost exclusively expressed in lung pericytes. Evidence from our research demonstrates that the disruption of AT2R (AT2R-/y), is associated with a surge in oxidative stress and impaired lung permeability, which were further intensified by Hyperoxic Acute Lung Injury (HALI). With aging, AT2R-/y mice show an increase in oxidative stress, premature enlargement of airspaces, as well as increased mortality when exposed to hyperoxia as compared to age-matched WT mice. Our investigation into Losartan, an AT1R blocker, suggests that its primary HALI lung-protective effects are channeled through AT2R, as its protective benefits are absent in AT2R-/y mice. Importantly, a non-peptide AT2R agonist, Compound 21 (C21), successfully reverses lung oxidative stress and TGFβ activation in wild-type (WT) mice exposed to HALI. These findings suggest a possible paradigm shift in the therapeutic approach for lung injury and age-associated pulmonary dysfunction, from targeting AT1R with angiotensin receptor blockers (ARBs) towards boosting the protective function of AT2R | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Acute lung injury | |
| 650 | 4 | |a Angiotensin type 2 receptor | |
| 650 | 4 | |a Hyperoxic acute lung injury | |
| 650 | 4 | |a Lung RAS | |
| 650 | 4 | |a Renin-angiotensin signaling system | |
| 650 | 7 | |a Receptor, Angiotensin, Type 2 |2 NLM | |
| 650 | 7 | |a Angiotensin II Type 1 Receptor Blockers |2 NLM | |
| 650 | 7 | |a Angiotensin Receptor Antagonists |2 NLM | |
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| 700 | 1 | |a Damarla, Mahendra |e verfasserin |4 aut | |
| 700 | 1 | |a Malinina, Alla |e verfasserin |4 aut | |
| 700 | 1 | |a Dikeman, Dustin |e verfasserin |4 aut | |
| 700 | 1 | |a Marx, Ruth |e verfasserin |4 aut | |
| 700 | 1 | |a Nader, Monica M |e verfasserin |4 aut | |
| 700 | 1 | |a Abadir, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Walston, Jeremy |e verfasserin |4 aut | |
| 700 | 1 | |a Neptune, Enid |e verfasserin |4 aut | |
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