A new paradigm of sodium regulation in inflammation and hypertension

Abstract

Dysregulation of sodium (Na⁺) balance is a major cause of hypertensive cardiovascular disease. The current dogma is that interstitial Na⁺ readily equilibrates with plasma and that renal excretion and reabsorption is sufficient to regulate extracellular fluid volume and control blood pressure. These ideas have been recently challenged by the discovery that Na⁺ accumulates in tissues without commensurate volume retention and activates immune cells, leading to hypertension and autoimmune disease. However, objections have been raised to this new paradigm, with some investigators concerned about where and how salt is stored in tissues. Further concerns also include how Na⁺ is mobilized from tissue stores and how it interacts with various organ systems to cause hypertension and end-organ damage. This review assesses these two paradigms of Na⁺ regulation in the context of inflammation-mediated hypertension and cardiovascular disease pathogenesis. Also highlighted are future perspectives and important gaps in our understanding of how Na⁺ is linked to inflammation and hypertension. Understanding mechanisms of salt and body fluid regulation is the sine qua non of research efforts to identify therapeutic targets for hypertension and cardiovascular disease.

Keywords: hypertension; inflammation; sodium regulation.

Fig. 1.

A new paradigm of sodium regulation. Sodium accumulates in tissues in concentrations exceeding those in plasma. In addition to kidney and other regulatory systems including the renin-angiotensin-aldosterone system (RAAS), atrial natriuretic peptide (ANP), and the sympathetic nervous system (SNS), macrophages function in an extrarenal sodium regulatory mechanism in part by expressing and activating the transcription factor tonicity-responsive enhancer binding protein (TonEBP), which binds to and upregulates expression of the vascular endothelial growth factor (VEGF) C gene. VEGFC stimulates lymphatic capillary network formation and increases expression of endothelial nitric oxide synthase (eNOS) in interstitial cells, increasing Na⁺ clearance from the skin.