Skin tight: macrophage-specific COX-2 induction links salt handling in kidney and skin

Abstract

The relationship between dietary salt intake and the associated risk of hypertension and cardiovascular disease is an important public health concern. In this issue of the JCI, a study by Zhang and associates shows that consumption of a high-sodium diet induces expression of cyclooxygenase-2 (COX-2) in macrophages, resulting in enhanced levels of prostaglandin E2 (PGE2), autocrine activation of the macrophage E-prostanoid 4 (EP4) receptor, and subsequent triggering of parallel pathways in the kidney and in skin that help dispose of excess sodium. The authors found that blockade or genetic elimination of the COX-2/PGE2/EP4 receptor pathway in hematopoietic cells causes salt-sensitive hypertension in mice. These studies illuminate an unexpected central role for the macrophage in coordinating homeostatic responses to dietary salt intake and suggest a complex pathophysiology for hypertension associated with NSAID use.

Figure 1. The COX-2/mPGES-1/EP4 receptor pathway in macrophages maintains sodium homeostasis by influencing salt secretion in the kidney and extrarenal sodium storage.

In this issue, Zhang and colleagues demonstrate that a high-salt diet induces expression of COX-2, thereby enhancing PGE₂ production and autocrine EP4 receptor (EP4R) signaling. In mice lacking the COX-2/mPGES-1/EP4 receptor pathway in hematopoietic cells, extrarenal salt storage and sodium secretion by the kidney are dysfunctional, resulting in the development of hypertension.