CD70 Exacerbates Blood Pressure Elevation and Renal Damage in Response to Repeated Hypertensive Stimuli

Abstract

Rationale Accumulating evidence supports a role of adaptive immunity and particularly T cells in the pathogenesis of hypertension. Formation of memory T cells, which requires the co-stimulatory molecule CD70 on antigen presenting cells, is a cardinal feature of adaptive immunity. Objective To test the hypothesis that CD70 and immunological memory contribute to the blood pressure elevation and renal dysfunction mediated by repeated hypertensive challenges. Methods and Results We imposed repeated hypertensive challenges using either L-NAME/high salt or repeated ang II stimulation in mice. During these challenges effector memory T (TEM) cells accumulated in the kidney and bone marrow. In the L-NAME/high salt model, memory T cells of the kidney were predominant sources of IFN-γ and IL-17A, known to contribute to hypertension. L-NAME/high salt increased macrophage and dendritic cell surface expression of CD70 by 3 to 5-fold. Mice lacking CD70 did not accumulate TEM cells and did not develop hypertension to either high salt or the second ang II challenge and were protected against renal damage. Bone marrow residing TEM cells proliferated and redistributed to the kidney in response to repeated salt feeding. Adoptively transferred TEM cells from hypertensive mice homed to the bone marrow and spleen and expanded upon salt feeding of the recipient mice. Conclusions Our findings illustrate a previously undefined role of CD70 and long-lived TEM cells in the development of blood pressure elevation and end-organ damage that occur upon delayed exposure to mild hypertensive stimuli. Interventions to prevent repeated hypertensive surges could attenuate formation of hypertension-specific TEM cells.

Role of Axl in T-Lymphocyte Survival in Salt-Dependent Hypertension

“…Production of IFN-γ by CD4 + and CD8 + T cells was recently shown to contribute to BP increase and kidney damage after repeated hypertensive stimuli 17 . Similar to our report in Axl chimeras 15 , we found reduction in arterial expression of IFN-γ (and Th1-dependent pathways) in Axl −/− mice after 6 weeks of DOCA-salt (not shown).…”

“…Adaptive immune cells such as T lymphocytes contribute to vascular dysfunction and DOCA-salt hypertension 16 . Recent study showed that both CD4 + and CD8 + T cells producing interferon gamma (IFN-γ) are involved in elevation of blood pressure and kidney damage after repeated hypertensive stimuli 17 . Interestingly, the Th1 response in the retina was also shown to be regulated through Axl/Mertk in mice 18 .…”

Interactions Between the Immune and the Renin–Angiotensin Systems in Hypertension

“…After infiltrating these tissues, mononuclear cells release ROS and inflammatory cytokines that regulate tissue injury and alter the release of vasoactive mediators, leading to endothelial dysfunction and/or sodium retention. Ongoing studies continue to parse actions of myeloid and T lymphocyte subpopulations in hypertension, and recent data indicate that distinct pro-inflammatory subsets within these broad populations, for example effector memory T cells, 87, 88 play important roles in blood pressure elevation and consequent target organ damage. By contrast, unique anti-inflammatory immune cell populations, including myeloid-derived suppressor cells and Tregs, can attenuate hypertension.…”

The Role of Dendritic and Endothelial Cells in Cardiorenal Syndrome

“…Furthermore, the depletion of DCs prior to I/R injury significantly reduced the kidney levels of TNF-α produced after the injury. In contrast, recent work showed the deleterious action of DCs during kidney injury induced by hypertensive stimuli [61, 62]. These findings suggest that DCs participate in the activation and initiation of immune response and are a key link between innate and adaptive immune responses for myocardial and renal I/R injury.…”