Mononuclear Phagocyte System Depletion Blocks Interstitial Tonicity-Responsive Enhancer Binding Protein/Vascular Endothelial Growth Factor C Expression and Induces Salt-Sensitive Hypertension in Rats

Abstract

Abstract-We showed recently that mononuclear phagocyte system (MPS) cells provide a buffering mechanism for salt-sensitive hypertension by driving interstitial lymphangiogenesis, modulating interstitial Na ϩ clearance, and increasing endothelial NO synthase protein expression in response to very high dietary salt via a tonicity-responsive enhancer binding protein/vascular endothelial growth factor C regulatory mechanism. We now tested whether isotonic saline and deoxycorticosterone acetate (DOCA)-salt treatment leads to a similar regulatory response in Sprague-Dawley rats. Male rats were fed a low-salt diet and received tap water (low-salt diet LSD), 1.0% saline (high-salt diet HSD), or DOCAϩ1.0% saline (DOCA-HSD). To test the regulatory role of interstitial MPS cells, we further depleted MPS cells with clodronate liposomes. HSD and DOCA-HSD led to Na ϩ accumulation in the skin, MPS-driven tonicity-responsive enhancer binding protein/ vascular endothelial growth factor C-mediated hyperplasia of interstitial lymph capillaries, and increased endothelial NO synthase protein expression in skin interstitium. Clodronate liposome MPS cell depletion blocked MPS infiltration in the skin interstitium, resulting in unchanged tonicity-responsive enhance binding protein/vascular endothelial growth factor C levels and absent hyperplasia of the lymph capillary network. Moreover, no increased skin endothelial NO synthase protein expression occurred in either clodronate liposome-treated HSD or DOCA-salt rats. Thus, absence of the MPS-cell regulatory response converted a salt-resistant blood-pressure state to a salt-sensitive state in HSD rats. Furthermore, salt-sensitive hypertension in DOCA-salt rats was aggravated. We conclude that MPS cells act as onsite controllers of interstitial volume and blood pressure homeostasis, providing a local regulatory salt-sensitive tonicity-responsive enhancer binding protein/ vascular endothelial growth factor C-mediated mechanism in the skin to maintain normal blood pressure in states of interstitial Na ϩ and Cl Ϫ accumulation. Failure of this physiological extrarenal regulatory mechanism leads to a salt-sensitive blood pressure response. (Hypertension. 2010;55:755-761.)

Immune cells control skin lymphatic electrolyte homeostasis and blood pressure

“…It assumes isosmolarity of body fluids among the bodily compartments (2). Along with others (4-7), we (8)(9)(10)(11)(12)(13)(14) showed earlier that electrolytes are distributed in a more complex 3-compartment model, in which intravascular and the interstitial fluids do not equilibrate as readily as believed (15,16). We underscored the importance of Na + binding to negatively charged proteoglycans in the skin, the largest organ with the most extracellular space (8,11).…”

Intradialytic Hypertension and its Association with Endothelial Cell Dysfunction

“…One possible explanation is that these patients have inadequate sodium removal during HD, resulting in extracellular volume expansion and total body sodium excess (19). In vitro, increasing evidence suggests that sodium can be stored osmotically inactive in the interstitium and lead to saltsensitive hypertension (20,21). In this study and in our previous studies (2,4), we have identified slightly lower ultrafiltration volumes among patients with intradialytic hypertension; thus, sodium balance may not be adequately restored by convection alone in these patients.…”

The role of renal microvascular disease and interstitial inflammation in salt-sensitive hypertension

“…Recent work by Titze and co-workers 64 have uncovered a new system that permits buffering the effects of salt intake on the blood pressure. Sodium is bound to proteoglycans in the interstitial space under the skin, where the local hypertonicity drives an increase of the lymphatics as a consequence of the production of vascular endothelial growth factor-C by the macrophages activated by the tonicity-responsive enhancer binding protein.…”