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

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