Immune Mechanisms in Arterial Hypertension

Abstract

Traditionally, arterial hypertension and subsequent end-organ damage have been attributed to hemodynamic factors, but increasing evidence indicates that inflammation also contributes to the deleterious consequences of this disease. The immune system has evolved to prevent invasion of foreign organisms and to promote tissue healing after injury. However, this beneficial activity comes at a cost of collateral damage when the immune system overreacts to internal injury, such as prehypertension. Renal inflammation results in injury and impaired urinary sodium excretion, and vascular inflammation leads to endothelial dysfunction, increased vascular resistance, and arterial remodeling and stiffening. Notably, modulation of the immune response can reduce the severity of BP elevation and hypertensive end-organ damage in several animal models. Indeed, recent studies have improved our understanding of how the immune response affects the pathogenesis of arterial hypertension, but the remarkable advances in basic immunology made during the last few years still await translation to the field of hypertension. This review briefly summarizes recent advances in immunity and hypertension as well as hypertensive end-organ damage.

Keywords: adaptive immunity; dendritic cells; hypertension; innate immunity.

Figure 1.

Polarization of CD4⁺ cells. Naive CD4⁺ T cells polarize into T_H1, T_H2, or T_H17 cells or Tregs.

Figure 2.

Role of dendritic cells as well as CD4⁺ and CD8⁺ cells in hypertension. Hypertension causes lipid oxidation in dendritic cells (DC) resulting in formation of isoketal adducts of various self-proteins. These isoketal-modified proteins behave like DAMPs and activate dendritic cells. The dendritic cells secrete cytokines such as IL-1, IL-6, and IL-23. In the renal lymph node or other tissues dendritic cells may activate CD8⁺ and CD4⁺ T cells that migrate into the kidney. CD8⁺ T cells release cytotoxins such as perforin and granzyme leading to apoptosis or cell death of peritubular capillaries causing vascular rarefaction. IL-17A and IFN-γ released from T_H17 and T_H1 activate the renin-angiotensin system and may stimulate or upregulate transport channels in the proximal and distal convoluted tubules, including the sodium hydrogen exchanger 3 (NHE3) and the sodium chloride cotransporter (NCC). Both in turn causes sodium and volume retention. Modified from reference 10.

Figure 3.

Working hypothesis describing the role of immunity in hypertension. Hypertensive factors such as Ang II, salt, or aldosterone lead to a cascade of events: They directly activate the innate immune system. This process includes complement activation and release of DAMPs, which can activate toll-like receptors and also the inflammasome. On the one hand these mechanisms damage the kidney directly. On the other hand, they promote the release of cryptic antigens and ROS production, isoketal formation, and alteration of proteins in dendritic cells. These nonself recognized proteins are presented to T cells. Polarized CD4⁺ and CD8⁺ T cells migrate into the heart, vessels, and kidney and mediate the hypertensive end-organ damage or aggravate this damage, as in the case of kidney arterial hypertension due to salt and volume retention. In addition activation of cells, such as monocytes/macrophages, γδ T cells, NK cells and ILCs may mediate or aggravate hypertensive renal injury. Modified from reference . CNS, central nervous system, nAg, neoantigen.