Role of B cells in Na+ barrier formation and salt-triggered

A high salt diet is common in Western society and closely related to vascular disease, elevated blood pressure (BP) and increased cardiovascular complications. Recent evidence has shown that sodium (Na+) can be stored in high amounts in the skin and that such Na+ storage is caused by excessive salt ingestion in humans and animals. High salt concentrations in the skin can also boost a pro- inflammatory response of immune cells. Interestingly, macrophages can reduce salt concentrations in tissue via activation of specific proteins and transcription factors by lymphatic clearance. This effect protects the organism from excessive salt storage, and uncontrolled inflammatory activity and hypertension. The role of B cells in a salt-rich microenvironment has not been clarified yet. Preliminary data indicate that B cells can boost the pro-inflammatory immune response, triggered by high Na+ storage in the skin but can also function as homeostatic regulators of skin Na+ clearance via the lymphatic system and additionally of BP. Our overarching hypothesis is that a high-salt diet adversely affects regulation of both BP and inflammation in inflammatory conditions through the accumulation of tissue Na +. Accordingly, we will address in preclinical studies the unknown role of B cells in Na+ barrier formation, as well as the salt-triggered pro-inflammatory immune and hypertensive responses. Using a novel mouse model with B-cell specific deletion of a transcription factor (Tonicity-Responsive Enhancer Binding Protein (TonEBP)) we will assess mechanisms of both pro-inflammatory and homeostatic B cell responses upon Na+ accumulation in the skin. With this project we want to determine if Na+ storage boosts pro-inflammatory antibody production in B cells and if B cells exert homeostatic regulatory activity by controlling lymphatic clearance from skin Na+ stores and provide a buffering mechanism for BP. To investigate if and how a high-salt diet may adversely affect BP regulation and inflammation through the accumulation of tissue Na+, this project addresses the role of TonEBP in salt-driven B cell maturation and antibody production as well as the role of Vascular Endothelial Growth Factor C (VEGF-C) and interferon gamma (INF-) in B cell dependent immune functions. Our studies could fundamentally change our view on the role of salt homeostasis by unravelling the effects of salt storage in the skin on B cells and will bring novel insights on how a high dietary salt intake may trigger a pro-inflammatory immune and hypertensive response. A positive outcome from these studies will have significant impact on future dietary recommendations and therapeutic approaches in various disease types, i.e. autoimmune diseases, infectious diseases and hypertension.

Target audience: general public 'Adaptive physiological water conservation explains hypertension and muscle catabolism in experimental chronic renal failure' Aim: The pathogenesis of hypertension yet has not been fully elucidated. As reported earlier, a high salt intake triggered an aestivation-like body water conservation response that lowered muscle mass and increased blood pressure. Here, we tested the hypothesis that a similar adaptive water conservation response occurs in experimental chronic renal failure. Methods: In four subsequent experiments in Sprague Dawley rats, we used surgical 5/6 renal mass reduction (5/6 Nx) to induce chronic renal failure. We studied solute and water excretion in 24-hour metabolic cage experiments, chronic blood pressure by radiotelemetry, chronic metabolic adjustment in liver and skeletal muscle by metabolomic analyses and selected enzyme activity measurements, body Na+, K+and water by dry ashing, and acute transepidermal water loss in conjunction with skin blood flow and intra-arterial blood pressure. Results: 5/6 Nx rats were polyuric because their kidneys could not sufficiently concentrate the urine. Physiological adaptation to this renal water loss included mobilization of nitrogen and energy from muscle for organic osmolyte production, parameters reflecting increased sympathetic nerve activity and water conservation with reduced skin blood flow, which by means of compensation reduced their transepidermal water loss. This complex physiologic-metabolic adjustment across multiple organs allowed the rats to stabilize their body water content despite persisting renal water loss, albeit at the expense of hypertension and catabolic mobilization of muscle protein. Conclusion: The hypertension in the applied model was associated with loss of water, and thus with hypovolaemia rather than hypervolaemia. This concept of the pathogenesis of hypertension is antipodal to the classic view that relies on hypervolaemia due to sodium retention. Physiological adaptation to body water loss, termed aestivation, is an evolutionary conserved survival strategy and an under-studied research area in medical physiology, which besides hypertension and muscle mass loss in chronic renal failure may explain many otherwise unexplainable phenomena in medicine.