Role of the Anaphylatoxin Receptor C5aR2 in Angiotensin II-Induced Hypertension and Hypertensive End-Organ Damage
Abstract BACKROUND Complement activation may facilitate hypertension through its effects on immune responses. The anaphylatoxin C5a, a major inflammatory effector, binds to the C5a receptors 1 and 2 (C5aR1, C5aR2). We have recently shown that C5aR1−/− mice have reduced hypertensive renal injury. The...
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| Veröffentlicht in: | American journal of hypertension 2024-09, Vol.37 (10), p.810-825 |
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| creator | Dreher, Leonie Bode, Marlies Ehnert, Nicolas Meyer-Schwesinger, Catherine Wiech, Thorsten Köhl, Jörg Huber, Tobias B Freiwald, Tilo Herrnstadt, Georg R Wenzel, Ulrich O |
| description | Abstract
BACKROUND
Complement activation may facilitate hypertension through its effects on immune responses. The anaphylatoxin C5a, a major inflammatory effector, binds to the C5a receptors 1 and 2 (C5aR1, C5aR2). We have recently shown that C5aR1−/− mice have reduced hypertensive renal injury. The role of C5aR2 in hypertension is unknown.
METHODS
For examination of C5aR2 expression on infiltrating and resident renal cells a tandem dye Tomato-C5aR2 knock-in reporter mouse was used. Human C5aR2 expression was analyzed in a single-cell RNAseq data set from the kidneys of hypertensive patients. Finally, we examined the effect of angiotensin II-induced hypertension in C5aR2-deficient mice.
RESULTS
Flow cytometric analysis of leukocytes isolated from kidneys of the reporter mice showed that dendritic cells are the major C5aR2-expressing population (34%) followed by monocyte/macrophages (30%) and neutrophils (14%). Using confocal microscopy C5aR2 was not detected in resident renal or cardiac cells. In the human kidney, C5aR2 was also mainly found in monocytes, macrophages, and dendritic cells with a significantly higher expression in hypertension (P |
| doi_str_mv | 10.1093/ajh/hpae082 |
| format | Article |
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BACKROUND
Complement activation may facilitate hypertension through its effects on immune responses. The anaphylatoxin C5a, a major inflammatory effector, binds to the C5a receptors 1 and 2 (C5aR1, C5aR2). We have recently shown that C5aR1−/− mice have reduced hypertensive renal injury. The role of C5aR2 in hypertension is unknown.
METHODS
For examination of C5aR2 expression on infiltrating and resident renal cells a tandem dye Tomato-C5aR2 knock-in reporter mouse was used. Human C5aR2 expression was analyzed in a single-cell RNAseq data set from the kidneys of hypertensive patients. Finally, we examined the effect of angiotensin II-induced hypertension in C5aR2-deficient mice.
RESULTS
Flow cytometric analysis of leukocytes isolated from kidneys of the reporter mice showed that dendritic cells are the major C5aR2-expressing population (34%) followed by monocyte/macrophages (30%) and neutrophils (14%). Using confocal microscopy C5aR2 was not detected in resident renal or cardiac cells. In the human kidney, C5aR2 was also mainly found in monocytes, macrophages, and dendritic cells with a significantly higher expression in hypertension (P < 0.05). Unilateral nephrectomy was performed followed by infusion of Ang II (0.75 ng/g/min) and a high salt diet in wildtype (n = 18) and C5aR2-deficient mice (n = 14). Blood pressure, renal injury (albuminuria, glomerular filtration rate, glomerular and tubulointerstitial injury, inflammation), and cardiac injury (cardiac fibrosis, heart weight, gene expression) did not differ between hypertensive wildtype and C5aR2−/− mice.
CONCLUSIONS
In summary, C5aR2 is mainly expressed in myeloid cells in the kidney in mice and humans but its deficiency has no effect on Ang II-induced hypertensive injury.
Graphical Abstract
Graphical Abstract</description><identifier>ISSN: 0895-7061</identifier><identifier>ISSN: 1941-7225</identifier><identifier>EISSN: 1941-7225</identifier><identifier>DOI: 10.1093/ajh/hpae082</identifier><identifier>PMID: 38934290</identifier><language>eng</language><publisher>US: Oxford University Press</publisher><subject>Angiotensin II ; Animals ; Blood Pressure ; Disease Models, Animal ; Humans ; Hypertension - metabolism ; Hypertension - physiopathology ; Hypertension, Renal ; Kidney - immunology ; Kidney - metabolism ; Kidney - pathology ; Kidney Diseases - chemically induced ; Kidney Diseases - metabolism ; Kidney Diseases - pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Nephritis ; Receptor, Anaphylatoxin C5a - genetics ; Receptor, Anaphylatoxin C5a - metabolism</subject><ispartof>American journal of hypertension, 2024-09, Vol.37 (10), p.810-825</ispartof><rights>The Author(s) 2024. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. 2024</rights><rights>The Author(s) 2024. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c208t-6c17acc687973f141ef9e8e6e664c2fd1dbc0e016895787db595572143aa566b3</cites><orcidid>0000-0001-7175-5062 ; 0009-0006-9301-6547</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,1583,27923,27924</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38934290$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dreher, Leonie</creatorcontrib><creatorcontrib>Bode, Marlies</creatorcontrib><creatorcontrib>Ehnert, Nicolas</creatorcontrib><creatorcontrib>Meyer-Schwesinger, Catherine</creatorcontrib><creatorcontrib>Wiech, Thorsten</creatorcontrib><creatorcontrib>Köhl, Jörg</creatorcontrib><creatorcontrib>Huber, Tobias B</creatorcontrib><creatorcontrib>Freiwald, Tilo</creatorcontrib><creatorcontrib>Herrnstadt, Georg R</creatorcontrib><creatorcontrib>Wenzel, Ulrich O</creatorcontrib><title>Role of the Anaphylatoxin Receptor C5aR2 in Angiotensin II-Induced Hypertension and Hypertensive End-Organ Damage</title><title>American journal of hypertension</title><addtitle>Am J Hypertens</addtitle><description>Abstract
BACKROUND
Complement activation may facilitate hypertension through its effects on immune responses. The anaphylatoxin C5a, a major inflammatory effector, binds to the C5a receptors 1 and 2 (C5aR1, C5aR2). We have recently shown that C5aR1−/− mice have reduced hypertensive renal injury. The role of C5aR2 in hypertension is unknown.
METHODS
For examination of C5aR2 expression on infiltrating and resident renal cells a tandem dye Tomato-C5aR2 knock-in reporter mouse was used. Human C5aR2 expression was analyzed in a single-cell RNAseq data set from the kidneys of hypertensive patients. Finally, we examined the effect of angiotensin II-induced hypertension in C5aR2-deficient mice.
RESULTS
Flow cytometric analysis of leukocytes isolated from kidneys of the reporter mice showed that dendritic cells are the major C5aR2-expressing population (34%) followed by monocyte/macrophages (30%) and neutrophils (14%). Using confocal microscopy C5aR2 was not detected in resident renal or cardiac cells. In the human kidney, C5aR2 was also mainly found in monocytes, macrophages, and dendritic cells with a significantly higher expression in hypertension (P < 0.05). Unilateral nephrectomy was performed followed by infusion of Ang II (0.75 ng/g/min) and a high salt diet in wildtype (n = 18) and C5aR2-deficient mice (n = 14). Blood pressure, renal injury (albuminuria, glomerular filtration rate, glomerular and tubulointerstitial injury, inflammation), and cardiac injury (cardiac fibrosis, heart weight, gene expression) did not differ between hypertensive wildtype and C5aR2−/− mice.
CONCLUSIONS
In summary, C5aR2 is mainly expressed in myeloid cells in the kidney in mice and humans but its deficiency has no effect on Ang II-induced hypertensive injury.
Graphical Abstract
Graphical Abstract</description><subject>Angiotensin II</subject><subject>Animals</subject><subject>Blood Pressure</subject><subject>Disease Models, Animal</subject><subject>Humans</subject><subject>Hypertension - metabolism</subject><subject>Hypertension - physiopathology</subject><subject>Hypertension, Renal</subject><subject>Kidney - immunology</subject><subject>Kidney - metabolism</subject><subject>Kidney - pathology</subject><subject>Kidney Diseases - chemically induced</subject><subject>Kidney Diseases - metabolism</subject><subject>Kidney Diseases - pathology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Nephritis</subject><subject>Receptor, Anaphylatoxin C5a - genetics</subject><subject>Receptor, Anaphylatoxin C5a - metabolism</subject><issn>0895-7061</issn><issn>1941-7225</issn><issn>1941-7225</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kEtLw0AUhQdRbH2s3MusRJDYmUkyj2Wp1QYKhaLrMJncNC3pTJpJxP57o63iytU9HD4O3A-hG0oeKVHhSG_KUVlrIJKdoCFVEQ0EY_EpGhKp4kAQTgfowvsNISTinJ6jQShVGDFFhmi3dBVgV-C2BDy2ui73lW7dx9riJRioW9fgSayXDPfN2K7WrgXr-5wkQWLzzkCOZ_samu_aWazt3-Id8NTmwaJZaYuf9Fav4AqdFbrycH28l-jtefo6mQXzxUsyGc8Dw4hsA26o0MZwKZQICxpRKBRI4MB5ZFiR0zwzBAjl_Y9CijyLVRwLRqNQ65jzLLxE94fdunG7DnybbtfeQFVpC67zaUgEkzRWMuzRhwNqGud9A0VaN-utbvYpJemX47R3nB4d9_TtcbjLtpD_sj9Se-DuALiu_nfpE90ahV4</recordid><startdate>20240916</startdate><enddate>20240916</enddate><creator>Dreher, Leonie</creator><creator>Bode, Marlies</creator><creator>Ehnert, Nicolas</creator><creator>Meyer-Schwesinger, Catherine</creator><creator>Wiech, Thorsten</creator><creator>Köhl, Jörg</creator><creator>Huber, Tobias B</creator><creator>Freiwald, Tilo</creator><creator>Herrnstadt, Georg R</creator><creator>Wenzel, Ulrich O</creator><general>Oxford University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-7175-5062</orcidid><orcidid>https://orcid.org/0009-0006-9301-6547</orcidid></search><sort><creationdate>20240916</creationdate><title>Role of the Anaphylatoxin Receptor C5aR2 in Angiotensin II-Induced Hypertension and Hypertensive End-Organ Damage</title><author>Dreher, Leonie ; Bode, Marlies ; Ehnert, Nicolas ; Meyer-Schwesinger, Catherine ; Wiech, Thorsten ; Köhl, Jörg ; Huber, Tobias B ; Freiwald, Tilo ; Herrnstadt, Georg R ; Wenzel, Ulrich O</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c208t-6c17acc687973f141ef9e8e6e664c2fd1dbc0e016895787db595572143aa566b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Angiotensin II</topic><topic>Animals</topic><topic>Blood Pressure</topic><topic>Disease Models, Animal</topic><topic>Humans</topic><topic>Hypertension - metabolism</topic><topic>Hypertension - physiopathology</topic><topic>Hypertension, Renal</topic><topic>Kidney - immunology</topic><topic>Kidney - metabolism</topic><topic>Kidney - pathology</topic><topic>Kidney Diseases - chemically induced</topic><topic>Kidney Diseases - metabolism</topic><topic>Kidney Diseases - pathology</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Nephritis</topic><topic>Receptor, Anaphylatoxin C5a - genetics</topic><topic>Receptor, Anaphylatoxin C5a - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dreher, Leonie</creatorcontrib><creatorcontrib>Bode, Marlies</creatorcontrib><creatorcontrib>Ehnert, Nicolas</creatorcontrib><creatorcontrib>Meyer-Schwesinger, Catherine</creatorcontrib><creatorcontrib>Wiech, Thorsten</creatorcontrib><creatorcontrib>Köhl, Jörg</creatorcontrib><creatorcontrib>Huber, Tobias B</creatorcontrib><creatorcontrib>Freiwald, Tilo</creatorcontrib><creatorcontrib>Herrnstadt, Georg R</creatorcontrib><creatorcontrib>Wenzel, Ulrich O</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>American journal of hypertension</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dreher, Leonie</au><au>Bode, Marlies</au><au>Ehnert, Nicolas</au><au>Meyer-Schwesinger, Catherine</au><au>Wiech, Thorsten</au><au>Köhl, Jörg</au><au>Huber, Tobias B</au><au>Freiwald, Tilo</au><au>Herrnstadt, Georg R</au><au>Wenzel, Ulrich O</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Role of the Anaphylatoxin Receptor C5aR2 in Angiotensin II-Induced Hypertension and Hypertensive End-Organ Damage</atitle><jtitle>American journal of hypertension</jtitle><addtitle>Am J Hypertens</addtitle><date>2024-09-16</date><risdate>2024</risdate><volume>37</volume><issue>10</issue><spage>810</spage><epage>825</epage><pages>810-825</pages><issn>0895-7061</issn><issn>1941-7225</issn><eissn>1941-7225</eissn><abstract>Abstract
BACKROUND
Complement activation may facilitate hypertension through its effects on immune responses. The anaphylatoxin C5a, a major inflammatory effector, binds to the C5a receptors 1 and 2 (C5aR1, C5aR2). We have recently shown that C5aR1−/− mice have reduced hypertensive renal injury. The role of C5aR2 in hypertension is unknown.
METHODS
For examination of C5aR2 expression on infiltrating and resident renal cells a tandem dye Tomato-C5aR2 knock-in reporter mouse was used. Human C5aR2 expression was analyzed in a single-cell RNAseq data set from the kidneys of hypertensive patients. Finally, we examined the effect of angiotensin II-induced hypertension in C5aR2-deficient mice.
RESULTS
Flow cytometric analysis of leukocytes isolated from kidneys of the reporter mice showed that dendritic cells are the major C5aR2-expressing population (34%) followed by monocyte/macrophages (30%) and neutrophils (14%). Using confocal microscopy C5aR2 was not detected in resident renal or cardiac cells. In the human kidney, C5aR2 was also mainly found in monocytes, macrophages, and dendritic cells with a significantly higher expression in hypertension (P < 0.05). Unilateral nephrectomy was performed followed by infusion of Ang II (0.75 ng/g/min) and a high salt diet in wildtype (n = 18) and C5aR2-deficient mice (n = 14). Blood pressure, renal injury (albuminuria, glomerular filtration rate, glomerular and tubulointerstitial injury, inflammation), and cardiac injury (cardiac fibrosis, heart weight, gene expression) did not differ between hypertensive wildtype and C5aR2−/− mice.
CONCLUSIONS
In summary, C5aR2 is mainly expressed in myeloid cells in the kidney in mice and humans but its deficiency has no effect on Ang II-induced hypertensive injury.
Graphical Abstract
Graphical Abstract</abstract><cop>US</cop><pub>Oxford University Press</pub><pmid>38934290</pmid><doi>10.1093/ajh/hpae082</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0001-7175-5062</orcidid><orcidid>https://orcid.org/0009-0006-9301-6547</orcidid></addata></record> |
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| ispartof | American journal of hypertension, 2024-09, Vol.37 (10), p.810-825 |
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| source | MEDLINE; Oxford University Press Journals All Titles (1996-Current) |
| subjects | Angiotensin II Animals Blood Pressure Disease Models, Animal Humans Hypertension - metabolism Hypertension - physiopathology Hypertension, Renal Kidney - immunology Kidney - metabolism Kidney - pathology Kidney Diseases - chemically induced Kidney Diseases - metabolism Kidney Diseases - pathology Male Mice Mice, Inbred C57BL Mice, Knockout Nephritis Receptor, Anaphylatoxin C5a - genetics Receptor, Anaphylatoxin C5a - metabolism |
| title | Role of the Anaphylatoxin Receptor C5aR2 in Angiotensin II-Induced Hypertension and Hypertensive End-Organ Damage |
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