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.