The Immune System in Hypertension: a Lost Shaker of Salt 2021 Lewis K. Dahl Memorial Lecture

Abstract

The seminal observations of Dr Lewis Dahl regarding renal mechanisms of hypertension remain highly relevant in light of more recent experiments showing that immune system dysfunction contributes to hypertension pathogenesis. Dr Dahl established that inappropriate salt retention in the kidney plays a central role via Ohm's Law in permitting blood pressure elevation. Nevertheless, inflammatory cytokines whose expression is induced in the early stages of hypertension can alter renal blood flow and sodium transporter expression and activity to foster renal sodium retention. By elaborating these cytokines and reactive oxygen species, myeloid cells and T lymphocytes can connect systemic inflammatory signals to aberrant kidney functions that allow sustained hypertension. By activating T lymphocytes, antigen-presenting cells such as dendritic cells represent an afferent sensing mechanism triggering T cell activation, cytokine generation, and renal salt and water reabsorption. Manipulating these inflammatory signals to attenuate hypertension without causing prohibitive systemic immunosuppression will pose a challenge, but disrupting actions of inflammatory mediators locally within the kidney may offer a path through which to target immune-mediated mechanisms of hypertension while capitalizing on Dr Dahl's key recognition of the kidney's importance in blood pressure regulation.

Keywords: blood pressure; hypertension; immune system; kidney; sodium transporters.

Figure 1.. Role of immune cells in the kidney during salt-sensitive hypertension.

With exposure to hypertensive stimuli, macrophages/monocytes, neutrophils, and dendritic cells (DCs) produce cytokines and ROS that directly target the kidney. Meanwhile, DCs trigger T cells to release cytokines and ROS in the kidney. Cytokines and ROS reduce renal blood flow but induce tubular injury, renal vascular inflammation, and sodium/water retention, consequently contributing to blood pressure elevation.

Figure 2.. Different subpopulations of activated T cells in hypertension.

In response to hypertensive stimuli, naïve T cells undergo activation by antigen-presenting cells to differentiate into different subtypes of activated T cells. CD8⁺ T cells, Th1, Th17, and γδ T cells, produce cytokines that contribute to hypertension, whereas Tregs suppress blood pressure levels.

Figure 3.. Potential targets for limiting DC maturation / activation.

During salt-sensitive hypertension, excess sodium (Na⁺) enters the DC through sodium transporters to activate DCs. Activating the serum/glucocorticoid kinase1 (SGK1) salt sensing kinase induces the NF-κB signaling pathway and fosters DC maturation. The mineralocorticoid receptor (MR) on DCs drives IL-6 release to activate T cells. By contrast, the ubiquitin editor A20 in dendritic cells restrains NF-κB-dependent DC maturation. When DCs mature, C-C Motif chemokine receptor 7 (CCR7) and costimulatory molecules including CD40, CD70, CD80, CD86 are expressed on the DC surface to guide DC interactions with the T cell receptor. Sodium transporters, the MR, SGK1, and A20 are potential targets for restraining DC activation and limiting the severity of immune-mediated hypertension.