Aldosterone, Inflammation, Immune System, and Hypertension

Abstract

Aldosterone is a mineralocorticoid hormone that controls body fluid and electrolyte balance. Excess aldosterone is associated with cardiovascular and metabolic diseases. Inflammation plays a critical role on vascular damage promoted by aldosterone and aggravates vascular abnormalities, including endothelial dysfunction, vascular remodeling, fibrosis and oxidative stress, and other manifestations of end-organ damage that are associated with hypertension, other forms of cardiovascular disease, and diabetes mellitus and the metabolic syndrome. Over the past few years, many studies have consistently shown that aldosterone activates cells of the innate and adaptive immune systems. Macrophages and T cells accumulate in the kidneys, heart, and vasculature in response to aldosterone, and infiltration of immune cells contributes to end-organ damage in cardiovascular and metabolic diseases. Aldosterone activates various subsets of innate immune cells such as dendritic cells and monocytes/macrophages, as well as adaptive immune cells such as T lymphocytes, and, by activation of mineralocorticoid receptors stimulates proinflammatory transcription factors and the production of adhesion molecules and inflammatory cytokines and chemokines. This review will briefly highlight some of the studies on the involvement of aldosterone in activation of innate and adaptive immune cells and its impact on the cardiovascular system. Since aldosterone plays a key role in many cardiovascular and metabolic diseases, these data will open up promising perspectives for the identification of novel biomarkers and therapeutic targets for prevention and treatment of diseases associated with increased levels of aldosterone, such as arterial hypertension, obesity, the metabolic syndrome, and heart failure.

Keywords: adaptive immune response; blood pressure; dendritic cells; hypertension; inflammation; innate immune response; lymphocytes; mineralocorticoid receptor; monocytes/macrophages.

Graphical Abstract

Figure 1.

Aldosterone and production of inflammatory mediators. Aldosterone induces the production of inflammatory mediators either through activation of mineralocorticoid receptors (MRs) or G-protein-coupled estrogen receptors (GPERs). The dashed line arrows indicate mechanisms not depicted in the figure. Abbreviations: Aldo, aldosterone; AP-1, activator protein-1; ATP, adenosine triphosphate; Ca²⁺, calcium; Col I, Collagen type I; COX-2, cyclooxygenase-2; CRP, C-reactive protein; DAMPs, damage-associated molecular patterns; ERK, extracellular signal-regulated kinase; IFN, interferon; IL, interleukin; K⁺, potassium; κBRE, nuclear factor-κB (NF-κB) response element; MCP-1, macrophage chemoattractant protein-1; MRE, MR response element; NADPH, reduced nicotinamide adenine dinucleotide phosphate; NF-κB, nuclear factor-κB; NGAL, neutrophil gelatinase-associated lipocalin; NLRP3, NOD-like receptor pyrin-domain containing protein 3; OPN, osteopontin; P2RX7, P2X purinoceptor 7; PI3K, phosphoinositide 3-kinase; ROS, reactive oxygen species; TGF, transforming growth factor; TLR, Toll-like receptor; TNF, tumor necrosis factor; TRE, 12-O-tetradecanoylphorbol-13-acetate response element (AP-1 response element); VCAM-1, vascular cell adhesion molecule-1.

Figure 2.

Aldosterone and activation of adaptive immune cells. Aldosterone induces activation of dendritic cells and increased polarization of CD4⁺ naive T cells into Th17, Th1, and decreased Treg cells. Aldosterone also increases recruitment of B lymphocytes and activation of CD8⁺ T cells. Abbreviations: IFN, interferon; IL, interleukin; TGF, transforming growth factor; Th, T helper cells; TNF, tumor necrosis factor; Treg, T regulatory cells.

Figure 3.

Aldosterone and immune responses in cardiovascular diseases. Excess aldosterone production occurring in diseases such as essential hypertension, primary aldosteronism, diabetes mellitus, and obesity contributes to increase blood pressure (BP). Over time, elevated BP, and/or aldosterone cause renal and vascular injury, which activates the innate and adaptive immune systems causing further tissue injury and thereafter exacerbating the detrimental effects of the initial disease. Abbreviations: ATP, adenosine triphosphate; DAMPs, damage-associated molecular patterns; DCs, dendritic cells; IFN, interferon; IL, interleukin; MΦ, macrophage; Ne, neutrophil; ROS, reactive oxygen species; Tc, cytotoxic T cells; TGF, transforming growth factor; Th, T helper cells; TNF, tumor necrosis factor; Treg, T regulatory cells.