Abstract 051: The Role of Immunological Memory in Hypertension
Immunological memory provides protection to repeated antigen challenges and is a cardinal feature of adaptive immunity. We have previously shown that adaptive immunity contributes to hypertension and have observed memory T cells in several models. We hypothesized that memory T cells contribute to long-term renal damage in response to repeated hypertensive challenges. To impose repeated episodes of hypertension, we treated C57BL/6 mice with L-NAME (0.5mg/ml) in drinking water for two weeks, allowed a two-week normotensive interval and then fed high salt (4% NaCl) for three weeks. L-NAME followed by high salt increased SBP to 151 ± 14 mmHg and caused a two-fold increase in CD4+ and CD8+ memory T cells in the kidney and bone marrow, as identified by the surface marker CD44hi. Intracellular staining showed that memory T cells were predominant sources of the inflammatory cytokines IL-17A and IFN-γ. Development and reactivation of memory T cells require the interaction of CD27 on T cells with CD70 on antigen presenting cells. Flow cytometry revealed that L-NAME/High salt increased expression of CD70 on splenic macrophages by 5-fold and dendritic cells by 3-fold. Because memory T cells are a major source of IFN-γ, we examined the hypertensive response to the L-NAME/high salt protocol in IFN-γ-/- mice. The hypertension caused by L-NAME was identical between WT, CD70-/- and IFN-γ-/- mice. In contrast, the hypertension induced by subsequent salt administration was markedly attenuated in CD70-/- mice (123 ± 1.3 mmHg, p<0.02). Likewise, mice lacking IFN-γ developed blunted hypertension during the salt-feeding phase (127.6 ± 5.5 mmHg, p<0.04). Interestingly, CD70-/- and IFN-γ-/- mice failed to develop memory T cell formation in the kidney. The L-NAME/high salt caused striking albuminuria and increased urinary N-gal in WT mice, and these were absent in CD70-/- and IFN-γ-/- mice. In contrast, L-NAME/high salt had no effect on renal angiotensinogen levels. Thus, repeated hypertensive stimuli lead to accumulation of long-lived effector memory T cells that are major sources of inflammatory cytokines, which in turn promote renal dysfunction, salt sensitivity and hypertension. These studies provide further insight into how the adaptive immune system promotes hypertension.
Author Disclosures: H.A. Itani: None. L. Xiao: None. M.A. Saleh: None. J. Wu: None. B.L. Dale: None. N.R. Barbaro: None. J.D. Foss: None. A. Kirabo: None. A.E. Norlander: None. W. Chen: None. R. Suto: None. L. Navar: None. K.E. Bernstein: None. D.G. Harrison: None.
- © 2015 by American Heart Association, Inc.