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

Abstract

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.

Body Fluid-Independent Effects of Dietary Salt Consumption in Chronic Kidney Disease

“…Also, their dialysis patients showed an increased lymphangiogenesis in skin biopsies. In type 1 diabetic patients, which share the trait of salt-sensitivity with CKD patients, our group was also able to show that these patients had higher skin lymphatic microvessel density in low salt conditions when compared to healthy controls [100]. This might reflect a higher skin sodium content in these patients, even in low dietary salt conditions.…”

Perturbed body fluid distribution and osmoregulation in response to high salt intake in patients with hereditary multiple exostoses

“…On day eight of our intervention a new steady state in sodium and water balance is expected to be achieved [ 45 ]. Furthermore, previous studies showed significant tissue remodeling and local osmoregulatory responses after one week of HSD [ [27] , [46] ]. However, certain limitations need to be considered.…”

Lymphatic vessel: Origin, heterogeneity, biological functions and therapeutic targets

“…Wenstedt et al observed that salt-sensitive increases in blood pressure in individuals with Type 1 diabetes may be linked to the absence of macrophages and thus reduced lymphangiogenesis. 252 Wu et al demonstrated that diabetes-induced ROS-activated c-Src-dependent phosphorylation of VEGFR3 and upregulation of epsin expression, causing VEGFR3 degradation via the interaction between epsin and VEGFR3, ultimately leading to impaired lymphangiogenesis. 253 In patients with Type 2 diabetes, increased lymphatic permeability has been demonstrated to lead to lymphatic vessel dysfunction.…”