Mosaic theory revised: inflammation and salt play central roles in arterial hypertension

Fig. 1. Revised version of the mosaic theory of hypertension. Salt and immune cells are placed in the center because they influence all other mosaic pieces. RAAS renin–angiotensin–aldosterone system, AT1R Ang II type 1 receptor, ENaC epithelial sodium channel

Fig. 2. Overview of immune cells that influence BP- and hypertension-mediated end-organ damage. PMNs polymorphonuclear neutrophils, M/Ms monocytes/macrophages, MDSCs myeloid-derived suppressor cells, DCs dendritic cells, NKT cells natural killer T cells, NK cells natural killer cells, CD4+ cluster of differentiation 4-positive cells, CD8+ cluster of differentiation 8-positive cells, Tregs regulatory T cells

Fig. 3. In monocytes/macrophages, high-salt enters proinflammatory cells via NCX1, causing NFAT5 expression and subsequent NO production by NOS2. In addition, proinflammatory cytokines such as IL-1β, IL-6, and TNF-α are released in response to high salt. In T cells, sodium enters the cell through the NKCC1 transporter, resulting in the upregulation of NFAT5 and its downstream target SGK1. Upregulation of the TH17 transcription marker RORγt mediates the transcription and translation of IL-23R, which is essential for TH17 induction and the secretion of IL-17a. NCX1 sodium calcium exchanger 1, NKCC1 sodium potassium chloride cotransporter, NOS2 nitric oxide synthase, NO nitric oxide, IL interleukin, TNF tumor necrosis factor, SGK1 serum glucocorticoid-regulated kinase, NFAT5 nuclear factor of activated T cells, RORγt retinoic-acid receptor-related orphan nuclear receptor gamma, M/M monocyte/macrophage

Fig. 4. A The classic effect of the MR is to promote renal sodium reabsorption by increasing the abundance of the epithelial sodium channel (ENaC) on the apical membrane of epithelial cells in the collecting duct after binding to its classic ligand aldosterone. B Second, it became clear that MR signaling in endothelial cells, VSMCs and cardiomyocytes promotes hypertension and fibrosis. C Third and more recently, it was discovered that MR signaling in innate and adaptive immune cells can cause hypertension and hypertensive end-organ damage. The effect of mineralocorticoid is conveyed via the ligand-activated translocation of cytosolic MR into the nucleus, where it binds to a specific DNA sequence known as the hormone response element (HRE) and initiates proinflammatory gene expression, inducing an M1 cascade with increased generation of ROS and M1 markers, as well as the secretion of MMPs and cytokines. In T cells, MR interacts with NFAT1 and AP-1 and promotes differentiation toward IFN-γ- and IL-17A-producing T-cell populations. ENaC epithelial sodium channel, ROMK renal outer medullary potassium channel, MR mineralocorticoid receptor, VSMC vascular smooth muscle cell, M/Ms…

Fig. 5. MR activation as a third signal in the immunological synapse in T-cell activation. T cells require three signals for activation: signals 1, 2, and 3. Signal 1 is T-cell receptor recognition of specific antigenic peptides presented on APCs. Signal 2 is costimulation, which involves interactions between CD80 and CD86 on APCs and CD28 on T cells. Signal 3 involves the stimulation of receptors outside of the immunologic synapse by hormones, cytokines, and danger signals present in the inflammatory milieu. MR signaling is a new signal 3 for lymphocytes associated with arterial hypertension. MR on T cells stimulates the production of IFN-γ, resulting in hypertension and cardiovascular fibrosis. DC dendritic cell, MHC major histocompatibility complex, TCR T-cell receptor, CD cluster of differentiation, AP-1 activator protein 1, NFAT1 nuclear factor of activated T cells 1, IL interleukin, IFN interferon

Fig. 6. Anti-inflammatory effect of AT1 receptor activation on inflammatory cells. Ang II angiotensin II, AT1 receptor angiotensin type 1 receptor, TNF tumor necrosis factor, IL interleukin, IFN interferon, M/Ms monocytes/macrophages