Primary essential hypertension is the major cardiovascular disease risk factor. Dietary salt intake is a putative driving force of blood pressure elevation;however, the mechanisms of this effect remain unclear. The central nervous system, heart and blood vessels, and kidney are primary participants and the kidney is the putative grand regulator of salt disposition and blood pressure. The overall goal of this work is t address whether or not local regulation of skin electrolyte metabolism is important for blood pressure control. Clinical evidence from pilot studies in humans and preliminary experimental data accumulated in our laboratory, support this hypothesis. Our data point to macrophage-derived vascular endothelial growth factor C (VEGF-C) as a crucial factor controlling skin electrolyte homeostasis. VEGF-C promotes interstitial electrolyte clearance through the cutaneous lymph capillary network. Macrophages induce hyperplasia of subcutaneous lymph capillaries after sensing local Na+ or Cl- overload in the interstitium. The sensing function is accomplished by binding of the transcription factor tonicity-enhancer binding protein (TonEBP) to the promoter region of the VEGF-C gene. The cells exert their regulatory function by increasing VEGF-C expression and secretion. Blockade of this VEGF-C response from macrophages leads to skin electrolyte accumulation and arterial hypertension. We propose a comprehensive program to characterize the importance of TonEBP for macrophage-driven lymphatic regulation of skin electrolyte homeostasis in vivo (Aim 1). We will address whether or not disruption of subcutaneous lymph capillaries by selective VEGF-C depletion in the skin will lead to specific changes in skin electrolyte composition and increase blood pressure systemically (Aim 2). Finally, we will test whether macrophage-derived VEGF-C exerts its blood pressure-lowering effect via receptor binding to blood vessels, or by binding to cutaneous lymph vessels (Aim 3).
Elevated blood pressure is a major cause for heart attacks and stroke. We have found that salt and water metabolism in the skin is important for blood pressure regulation. The studies in this proposal will determine in mouse pre-clinical models how immune cells control salt and water balance in the skin and thereby control blood pressure.
| Crescenzi, Rachelle; Marton, Adriana; Donahue, Paula M C et al. (2018) Tissue Sodium Content is Elevated in the Skin and Subcutaneous Adipose Tissue in Women with Lipedema. Obesity (Silver Spring) 26:310-317 |
| Kitada, Kento; Daub, Steffen; Zhang, Yahua et al. (2017) High salt intake reprioritizes osmolyte and energy metabolism for body fluid conservation. J Clin Invest 127:1944-1959 |
| Rakova, Natalia; Kitada, Kento; Lerchl, Kathrin et al. (2017) Increased salt consumption induces body water conservation and decreases fluid intake. J Clin Invest 127:1932-1943 |
| Titze, Jens; Luft, Friedrich C (2017) Speculations on salt and the genesis of arterial hypertension. Kidney Int 91:1324-1335 |
| Schatz, Valentin; Neubert, Patrick; Schröder, Agnes et al. (2017) Elementary immunology: Na+ as a regulator of immunity. Pediatr Nephrol 32:201-210 |
| Birukov, Anna; Rakova, Natalia; Lerchl, Kathrin et al. (2016) Ultra-long-term human salt balance studies reveal interrelations between sodium, potassium, and chloride intake and excretion. Am J Clin Nutr 104:49-57 |
| Titze, Jens; Rakova, Natalia; Kopp, Christoph et al. (2016) Balancing wobbles in the body sodium. Nephrol Dial Transplant 31:1078-81 |
| Johnson, Randall S; Titze, Jens; Weller, Richard (2016) Cutaneous control of blood pressure. Curr Opin Nephrol Hypertens 25:11-5 |
| Binger, Katrina J; Gebhardt, Matthias; Heinig, Matthias et al. (2015) High salt reduces the activation of IL-4- and IL-13-stimulated macrophages. J Clin Invest 125:4223-38 |
| Jantsch, Jonathan; Schatz, Valentin; Friedrich, Diana et al. (2015) Cutaneous Na+ storage strengthens the antimicrobial barrier function of the skin and boosts macrophage-driven host defense. Cell Metab 21:493-501 |
Showing the most recent 10 out of 23 publications
