Obligatory role for B cells in the development of angiotensin II-dependent hypertension

Christopher Te-Lee Chan, Christopher G Sobey, Maggie Lieu, Dorota M Ferens, Michelle M Kett, Henry Diep, Helena Hyun Ah Kim, Shalini M Krishnan, Caitlin V Lewis, Ekaterina Salimova, Peter G Tipping, Antony Vinh, Chrishan S Samuel, Karlheinz Peter, Tomasz J Guzik, Tin S Kyaw, Ban-Hock Toh, Alexander Bobik, Grant R Drummond

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Abstract

Clinical hypertension is associated with raised serum IgG antibodies. However, whether antibodies are causative agents in hypertension remains unknown. We investigated whether hypertension in mice is associated with B-cell activation and IgG production and moreover whether B-cell/IgG deficiency affords protection against hypertension and vascular remodeling. Angiotensin II (Ang II) infusion (0.7 mg/kg per day; 28 days) was associated with (1) a 25 increase in the proportion of splenic B cells expressing the activation marker CD86, (2) an 80 increase in splenic plasma cell numbers, (3) a 500 increase in circulating IgG, and (4) marked IgG accumulation in the aortic adventitia. In B-cell-activating factor receptor-deficient (BAFF-R-/-) mice, which lack mature B cells, there was no evidence of Ang II-induced increases in serum IgG. Furthermore, the hypertensive response to Ang II was attenuated in BAFF-R-/- (Delta30+/-4 mm Hg) relative to wild-type (Delta41+/-5 mm Hg) mice, and this response was rescued by B-cell transfer. BAFF-R-/- mice displayed reduced IgG accumulation in the aorta, which was associated with 80 fewer aortic macrophages and a 70 reduction in transforming growth factor-beta expression. BAFF-R-/- mice were also protected from Ang II-induced collagen deposition and aortic stiffening (assessed by pulse wave velocity analysis). Finally, like BAFF-R deficiency, pharmacological depletion of B cells with an anti-CD20 antibody attenuated Ang II-induced hypertension by approximately 35 . Hence, these studies demonstrate that B cells/IgGs are crucial for the development of Ang II-induced hypertension and vessel remodeling in mice. Thus, B-cell-targeted therapies-currently used for autoimmune diseases-may hold promise as future treatments for hypertension.
Original languageEnglish
Pages (from-to)1023 - 1033
Number of pages11
JournalHypertension
Volume66
Issue number5
DOIs
Publication statusPublished - 2015

Cite this

@article{e160f32834664fe297f830b9d4551683,
title = "Obligatory role for B cells in the development of angiotensin II-dependent hypertension",
abstract = "Clinical hypertension is associated with raised serum IgG antibodies. However, whether antibodies are causative agents in hypertension remains unknown. We investigated whether hypertension in mice is associated with B-cell activation and IgG production and moreover whether B-cell/IgG deficiency affords protection against hypertension and vascular remodeling. Angiotensin II (Ang II) infusion (0.7 mg/kg per day; 28 days) was associated with (1) a 25 increase in the proportion of splenic B cells expressing the activation marker CD86, (2) an 80 increase in splenic plasma cell numbers, (3) a 500 increase in circulating IgG, and (4) marked IgG accumulation in the aortic adventitia. In B-cell-activating factor receptor-deficient (BAFF-R-/-) mice, which lack mature B cells, there was no evidence of Ang II-induced increases in serum IgG. Furthermore, the hypertensive response to Ang II was attenuated in BAFF-R-/- (Delta30+/-4 mm Hg) relative to wild-type (Delta41+/-5 mm Hg) mice, and this response was rescued by B-cell transfer. BAFF-R-/- mice displayed reduced IgG accumulation in the aorta, which was associated with 80 fewer aortic macrophages and a 70 reduction in transforming growth factor-beta expression. BAFF-R-/- mice were also protected from Ang II-induced collagen deposition and aortic stiffening (assessed by pulse wave velocity analysis). Finally, like BAFF-R deficiency, pharmacological depletion of B cells with an anti-CD20 antibody attenuated Ang II-induced hypertension by approximately 35 . Hence, these studies demonstrate that B cells/IgGs are crucial for the development of Ang II-induced hypertension and vessel remodeling in mice. Thus, B-cell-targeted therapies-currently used for autoimmune diseases-may hold promise as future treatments for hypertension.",
author = "Chan, {Christopher Te-Lee} and Sobey, {Christopher G} and Maggie Lieu and Ferens, {Dorota M} and Kett, {Michelle M} and Henry Diep and Kim, {Helena Hyun Ah} and Krishnan, {Shalini M} and Lewis, {Caitlin V} and Ekaterina Salimova and Tipping, {Peter G} and Antony Vinh and Samuel, {Chrishan S} and Karlheinz Peter and Guzik, {Tomasz J} and Kyaw, {Tin S} and Ban-Hock Toh and Alexander Bobik and Drummond, {Grant R}",
year = "2015",
doi = "10.1161/HYPERTENSIONAHA.115.05779",
language = "English",
volume = "66",
pages = "1023 -- 1033",
journal = "Hypertension",
issn = "0194-911X",
publisher = "American Heart Association",
number = "5",

}

Obligatory role for B cells in the development of angiotensin II-dependent hypertension. / Chan, Christopher Te-Lee; Sobey, Christopher G; Lieu, Maggie; Ferens, Dorota M; Kett, Michelle M; Diep, Henry; Kim, Helena Hyun Ah; Krishnan, Shalini M; Lewis, Caitlin V; Salimova, Ekaterina; Tipping, Peter G; Vinh, Antony; Samuel, Chrishan S; Peter, Karlheinz; Guzik, Tomasz J; Kyaw, Tin S; Toh, Ban-Hock; Bobik, Alexander; Drummond, Grant R.

In: Hypertension, Vol. 66, No. 5, 2015, p. 1023 - 1033.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Obligatory role for B cells in the development of angiotensin II-dependent hypertension

AU - Chan, Christopher Te-Lee

AU - Sobey, Christopher G

AU - Lieu, Maggie

AU - Ferens, Dorota M

AU - Kett, Michelle M

AU - Diep, Henry

AU - Kim, Helena Hyun Ah

AU - Krishnan, Shalini M

AU - Lewis, Caitlin V

AU - Salimova, Ekaterina

AU - Tipping, Peter G

AU - Vinh, Antony

AU - Samuel, Chrishan S

AU - Peter, Karlheinz

AU - Guzik, Tomasz J

AU - Kyaw, Tin S

AU - Toh, Ban-Hock

AU - Bobik, Alexander

AU - Drummond, Grant R

PY - 2015

Y1 - 2015

N2 - Clinical hypertension is associated with raised serum IgG antibodies. However, whether antibodies are causative agents in hypertension remains unknown. We investigated whether hypertension in mice is associated with B-cell activation and IgG production and moreover whether B-cell/IgG deficiency affords protection against hypertension and vascular remodeling. Angiotensin II (Ang II) infusion (0.7 mg/kg per day; 28 days) was associated with (1) a 25 increase in the proportion of splenic B cells expressing the activation marker CD86, (2) an 80 increase in splenic plasma cell numbers, (3) a 500 increase in circulating IgG, and (4) marked IgG accumulation in the aortic adventitia. In B-cell-activating factor receptor-deficient (BAFF-R-/-) mice, which lack mature B cells, there was no evidence of Ang II-induced increases in serum IgG. Furthermore, the hypertensive response to Ang II was attenuated in BAFF-R-/- (Delta30+/-4 mm Hg) relative to wild-type (Delta41+/-5 mm Hg) mice, and this response was rescued by B-cell transfer. BAFF-R-/- mice displayed reduced IgG accumulation in the aorta, which was associated with 80 fewer aortic macrophages and a 70 reduction in transforming growth factor-beta expression. BAFF-R-/- mice were also protected from Ang II-induced collagen deposition and aortic stiffening (assessed by pulse wave velocity analysis). Finally, like BAFF-R deficiency, pharmacological depletion of B cells with an anti-CD20 antibody attenuated Ang II-induced hypertension by approximately 35 . Hence, these studies demonstrate that B cells/IgGs are crucial for the development of Ang II-induced hypertension and vessel remodeling in mice. Thus, B-cell-targeted therapies-currently used for autoimmune diseases-may hold promise as future treatments for hypertension.

AB - Clinical hypertension is associated with raised serum IgG antibodies. However, whether antibodies are causative agents in hypertension remains unknown. We investigated whether hypertension in mice is associated with B-cell activation and IgG production and moreover whether B-cell/IgG deficiency affords protection against hypertension and vascular remodeling. Angiotensin II (Ang II) infusion (0.7 mg/kg per day; 28 days) was associated with (1) a 25 increase in the proportion of splenic B cells expressing the activation marker CD86, (2) an 80 increase in splenic plasma cell numbers, (3) a 500 increase in circulating IgG, and (4) marked IgG accumulation in the aortic adventitia. In B-cell-activating factor receptor-deficient (BAFF-R-/-) mice, which lack mature B cells, there was no evidence of Ang II-induced increases in serum IgG. Furthermore, the hypertensive response to Ang II was attenuated in BAFF-R-/- (Delta30+/-4 mm Hg) relative to wild-type (Delta41+/-5 mm Hg) mice, and this response was rescued by B-cell transfer. BAFF-R-/- mice displayed reduced IgG accumulation in the aorta, which was associated with 80 fewer aortic macrophages and a 70 reduction in transforming growth factor-beta expression. BAFF-R-/- mice were also protected from Ang II-induced collagen deposition and aortic stiffening (assessed by pulse wave velocity analysis). Finally, like BAFF-R deficiency, pharmacological depletion of B cells with an anti-CD20 antibody attenuated Ang II-induced hypertension by approximately 35 . Hence, these studies demonstrate that B cells/IgGs are crucial for the development of Ang II-induced hypertension and vessel remodeling in mice. Thus, B-cell-targeted therapies-currently used for autoimmune diseases-may hold promise as future treatments for hypertension.

UR - http://hyper.ahajournals.org/content/66/5/1023.full.pdf+html

U2 - 10.1161/HYPERTENSIONAHA.115.05779

DO - 10.1161/HYPERTENSIONAHA.115.05779

M3 - Article

VL - 66

SP - 1023

EP - 1033

JO - Hypertension

JF - Hypertension

SN - 0194-911X

IS - 5

ER -