Salt-sensitive blood pressure rise in type 1 diabetes patients is accompanied by disturbed skin macrophage influx and lymphatic dilation—a proof-of-concept study

Type 1 diabetes patients are more prone to have hypertension than healthy individuals, possibly mediated by increased blood pressure (BP) sensitivity to high salt intake. The classical concept proposes that the kidney is central in salt-mediated BP rises, by insufficient renal sodium excretion leading to extracellular fluid volume expansion. Recent animal-derived findings, however, propose a causal role for disturbance of macrophage-mediated lymphangiogenesis. Its relevance for humans, specifically type 1 diabetes patients, is unknown. The present study aimed to assess responses of type 1 diabetes patients to a dietary salt load with regard to BP, extracellular fluid volume (using precise iohexol measurements), and CD163+ macrophage and lymphatic capillary density in skin biopsies. Also, macrophage expression of HLA-DR (a proinflammatory marker) and CD206 (an anti-inflammatory marker) was assessed. Type 1 diabetes patients (n = 8) showed a salt-sensitive BP increase without extracellular fluid volume expansion. Whereas healthy controls (n = 12), who had no BP increase, showed increased skin CD163+ and HLA-DR+ macrophages and dilation of lymphatic skin vasculature after the dietary salt load, these changes were absent (and in case of HLA-DR more heterogenic) in type 1 diabetes patients. In conclusion, we show that salt sensitivity in type 1 diabetes patients cannot be explained by the classical concept of extracellular fluid volume expansion. Rather, we open up a potential role for macrophages and the lymphatic system. Future studies on hypertension and diabetes need to scrutinize these phenomena. Type 1 diabetes patients are more prone to have hypertension than healthy individuals, possibly mediated by increased blood pressure (BP) sensitivity to high salt intake. The classical concept proposes that the kidney is central in salt-mediated BP rises, by insufficient renal sodium excretion leading to extracellular fluid volume expansion. Recent animal-derived findings, however, propose a causal role for disturbance of macrophage-mediated lymphangiogenesis. Its relevance for humans, specifically type 1 diabetes patients, is unknown. The present study aimed to assess responses of type 1 diabetes patients to a dietary salt load with regard to BP, extracellular fluid volume (using precise iohexol measurements), and CD163+ macrophage and lymphatic capillary density in skin biopsies. Also, macrophage expression of HLA-DR (a proinflammatory marker) and CD206 (an anti-inflammatory marker) was assessed. Type 1 diabetes patients (n = 8) showed a salt-sensitive BP increase without extracellular fluid volume expansion. Whereas healthy controls (n = 12), who had no BP increase, showed increased skin CD163+ and HLA-DR+ macrophages and dilation of lymphatic skin vasculature after the dietary salt load, these changes were absent (and in case of HLA-DR more heterogenic) in type 1 diabetes patients. In conclusion, we show that salt sensitivity in type 1 diabetes patients cannot be explained by the classical concept of extracellular fluid volume expansion. Rather, we open up a potential role for macrophages and the lymphatic system. Future studies on hypertension and diabetes need to scrutinize these phenomena. Brief CommentaryEliane F.E. Wenstedt et al. BackgroundAlthough classically, the kidney is supposed to have a central role in the link between salt and hypertension, animal studies suggest a role for macrophages and lymphatic vessels of the skin. Translational SignificanceWe are, to our knowledge, the first to demonstrate that salt induces macrophage influx and lymphatic dilation in the skin of healthy humans, and that this process is disturbed in salt-sensitive type 1 diabetes patients. This agrees with the animal findings that macrophage-mediated lymphangiogenesis is protective against salt-sensitive hypertension development. Future human studies need to scrutinize these phenomena, in order to eventually develop better therapies. Eliane F.E. Wenstedt et al. Although classically, the kidney is supposed to have a central role in the link between salt and hypertension, animal studies suggest a role for macrophages and lymphatic vessels of the skin. We are, to our knowledge, the first to demonstrate that salt induces macrophage influx and lymphatic dilation in the skin of healthy humans, and that this process is disturbed in salt-sensitive type 1 diabetes patients. This agrees with the animal findings that macrophage-mediated lymphangiogenesis is protective against salt-sensitive hypertension development. Future human studies need to scrutinize these phenomena, in order to eventually develop better therapies.