Differential Effects of BAFF Neutralization and BAFF Receptor Inhibition on Angiotensin II‐Induced Hypertension in Mice

Abstract

IntroductionB cell activating factor (BAFF) is crucial for B cell survival and pharmacological depletion of BAFF is used clinically to treat autoimmune diseases. We have shown that BAFF‐receptor‐deficient (BAFF‐R−/−) mice ‐ which are devoid of mature B cells ‐ are protected from angiotensin II‐induced hypertension and vascular remodelling. However, whether pharmacological depletion of BAFF is a viable therapeutic strategy for hypertension remains to be established.MethodsHypertension was induced in male C57BL6J and BAFF‐R−/− mice by infusion of angiotensin II (0.7 mg/kg/d, s.c., 14 d). Normotensive mice were saline‐infused. Some mice were also treated with an anti‐BAFF neutralising monoclonal antibody (mAb) or isotype control (2mg/kg; i.v.), 14 d prior to and on the day of induction of hypertension. BP was monitored by tail cuff and vascular stiffening was measured by ultrasound. Leukocyte subsets were assessed by flow cytometry; serum BAFF and IgG were quantified by ELISA; and collagen levels in aortic sections were measured by masson's trichrome staining.ResultsAngiotensin II‐induced hypertension in wild type mice was NOT associated with changes in total CD19+ B cell or CD3+ T cell numbers in the spleen or bone marrow; however, there was evidence of B cell activation. Thus, angiotensin II‐treatment promoted a 1.4‐fold increase in B cell expression of the activation marker, CD86 (P<0.05) and elevated circulating IgG antibodies by 2‐fold (P<0.05). Compared to wild‐type mice, BAFF‐R−/− mice had markedly reduced numbers of CD19+ B cells in both their spleens and bone marrow (15% cf. wild type mice; P<0.01), as well as fewer T cells (20% cf. wild type mice; P<0.01). BAFF‐R−/− mice also had markedly reduced levels of circulating IgG (10% cf. wild type mice; P<0.001). Accordingly, BAFF‐R−/− mice displayed a blunted hypertensive response to angiotensin II (138±4 vs 160±3 mmHg in wild‐type mice; P<0.001) and were fully protected from cardiac hypertrophy, aortic fibrosis and vascular stiffening. Treatment with anti‐BAFF mAb reduced circulating BAFF levels by ~96% (P<0.001) and CD19+ B cell numbers in the spleen by 86% (P<0.001). However, anti‐BAFF mAb treatment was less effective than BAFF‐R deficiency at reducing CD19+ B cell numbers in the bone marrow with 40% of B cells remaining (P<0.05), and only reduced circulating IgG levels by 65% (P<0.01). Furthermore, anti‐BAFF treatment did not reduce CD3+ T cell numbers in the spleen or bone marrow, and was ineffective at preventing angiotensin II‐induced hypertension, cardiac hypertrophy and vascular remodelling and stiffening.ConclusionAnti‐BAFF mAb treatment was less effective than genetic deficiency of the BAFF‐R at protecting against angiotensin II‐induced hypertension. Thus, pharmacological depletion of BAFF may not be a viable therapeutic strategy for hypertension.Support or Funding InformationThis work was supported by the National Health and Medical Research Council of Australia (GNT1143674).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.