Targeting cytokine signaling in salt-sensitive hypertension

Abstract

Activated immune cell populations contribute to hypertension in part through inciting damage to the kidney and by provoking inappropriate sodium reabsorption in the nephron. Inflammatory mediators called cytokines produced by T lymphocytes and macrophages act on specific sodium transporters in the kidney, augmenting their activity or expression, with consequent expansion of intravascular fluid volume and cardiac output. The overlapping functions of these cytokines, each of which may activate multiple receptors, present challenges in precisely targeting inflammatory signaling cascades in hypertension. Moreover, broad immune suppression could expose the hypertensive patient to disproportional risks of infection or malignancy. Nevertheless, the possibility that incisive immunomodulatory therapies could provide cardiovascular and renal protection through both blood pressure-dependent and -independent mechanisms justifies comprehensive investigation into the relevant signaling pathways and tissue sites in which inflammatory cytokines function to exaggerate blood pressure elevation and target organ damage in hypertension.

Keywords: cytokine signaling; hypertension; organ damage.

Fig. 1.

Ligation of the IL-1R1 receptor on intrarenal myeloid cells inhibits nitric oxide synthase (NOS)2 expression, leading to reduced nitric oxide (NO) production. Binding of ANG II to the type 1 angiotensin receptor (AT₁R) on the medullary thick ascending limb (mTAL) epithelial cell in the kidney enhances TNF-α production, which inhibits NOS3 expression and thereby reduces NO production. In each case, the blunted NO generation permits augmented activity of the NKCC2 sodium cotransporter and exaggerated sodium reabsorption.