Renal Effects of Cytokines in Hypertension

Yi Wen; Steven D. Crowley

Disclosures

Curr Opin Nephrol Hypertens. 2018;27(2):70-76. 

In This Article

Immune Cells in Hypertension

Inflammatory cells are present in the kidneys of patients with severe hypertension as demonstrated in autopsy studies,[7] and animal models have demonstrated that myeloid cells from the innate immune system and lymphocytes from the adaptive immune system make distinct contributions to the pathogenesis of hypertension. Among the myeloid cell populations, circulating monocytes and tissue macrophages exacerbate both BP elevation and target organ damage in hypertension. Accordingly, deleting LysM-expressing macrophages attenuates endothelial dysfunction and hypertension during chronic infusion of angiotensin (Ang) II.[8] Such actions of macrophages to disrupt vascular function can provoke sodium retention in the kidney by disrupting renal blood flow. In multiple models, expression of the chemokine receptor CCR2 on monocytes facilitates their recruitment into the kidney with consequent exacerbations in hypertensive renal injury,[9,10] whereas the mononuclear cell chemokine CCL5 paradoxically protects the kidney from damage and fibrosis in hypertension by tempering CCR2-dependent infiltration of Ly6Chi inflammatory macrophages into the renal interstitium.[11] In contrast to the detrimental actions of proinflammatory macrophages in the kidney and vasculature during hypertension, VEGF-C-expressing macrophages in the skin stimulate lymphatic drainage of sodium from interstitial reservoirs back into the circulation to allow natriuresis and thereby limit BP elevation. Thus, macrophages can have diverse effects on intravascular volume and renal function, depending on their differentiation and tissue distribution[12,13]

Another myeloid cell subset, the dendritic cell, serves as a bridge between innate and adaptive immunity by processing and presenting specific antigens to T lymphocytes that in turn proliferate, differentiate, and secrete both reactive oxygen species and vasoactive cytokines that could play a role in BP elevation. Dendritic cells in the kidney invite renal infiltration of T cells,[14] and the presentation of antigen by dendritic cells to T cells in the context of appropriate costimulatory signals is required for the full manifestation of hypertension in multiple models.[15] Moreover, activated dendritic cells can transfer the susceptibility to hypertension but only the presence of responder T lymphocytes that can undergo activation.[16]

Once activated, the adaptive immune system plays a major role in the pathogenesis of sustained hypertension.[17] In a landmark study, Guzik et al.[18] established through adoptive transfer that T but not B lymphocytes are essential for the induction of hypertension and associated vascular dysfunction. Our group found that lymphocytes impair natriuresis during hypertension, possibly through the suppression in the kidney of NOS3 and COX-2.[19] Among the T-cell subsets, CD8+ rather than CD4+ T cells appear to mediate prominent prohypertensive actions of the adaptive immune system, including sodium retention and endothelial dysfunction. Although B lymphocytes in isolation do not drive BP elevation,[18] they may exacerbate hypertension by facilitating T-cell activation and consequent cytokine generation.[20,21] Thus, cells in both the innate and adaptive immune systems contribute to hypertension via actions in the vasculature and the kidney. Next, we focus on the specific actions of individual cytokines produced by these cells to drive renovascular dysfunction and/or renal sodium retention.

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