Sodium accumulation in the skin is associated with higher density of skin lymphatic vessels in patients with arterial hypertension

Abstract

Purpose: Recent studies, conducted mainly on the rodent model, have demonstrated that regulatory pathway in the skin provided by glycosaminoglycans, nuclear factor of activated T cells 5 (NFAT5), vascular endothelial growth factor C (VEGF-C) and process of lymphangiogenesis may play an important role in extrarenal regulation of sodium (Na⁺) balance, body water volume, and blood pressure. We aimed to investigate the concentrations and relations among the main factors of this pathway in human skin to confirm that this regulatory axis also exists in humans.

Patients and methods: Skin specimens from patients diagnosed with arterial hypertension and from control group were histologically and molecularly examined.

Results: The primary hypertensive and control groups did not differ in Na⁺ ​concentrations in the skin. However, the patients with hypertension and higher skin Na⁺ concentration had significantly greater density of skin lymphatic vessels. Higher skin Na⁺concentration was associated with higher skin water content. In turn, skin water content correlated with factors associated with lymphangiogenesis, i.e. NFAT5, VEGF-C, and podoplanin (PDPN) mRNA expression in the skin. The strong mutual pairwise correlations of the expressions of NFAT5, VEGF-C, vascular endothelial growth factor D (VEGF-D) and PDPN mRNA were noted in the skin in all of the studied groups.

Conclusions: Our study confirms that skin interstitium and the lymphatic system may be important players in the pathophysiology of arterial hypertension in humans. Based on the results of our study and existing literature in this field, we propose the hypothetical model which might explain the phenomenon of salt-sensitivity.

Keywords: Hyaluronic acid; Lymphangiogenesis; Salt-sensitivity; TonEBP/NFAT5; VEGF-C.