The skin renin-angiotensin system and hypertension: A TRAP for blood flow capture and water release

The skin, comprising the epidermis, dermis and subcutaneous tissue, is the largest organ of the body. The skin, not only separating and protecting the internal milieu from environmental stimuli but also receiving uninterruptedly the multiple intrinsic and extrinsic signals, undergoes various physiological functions in order to regulate the body homeostasis. These functions are mediated by local regulators, i.e., endocrine/paracrine factors, autonomic nerve fibers/neurotransmitters, neuropeptides, cytokines, and immune cells [1]. Such factors are also important in response to multiple stressors including solar radiation and biological, chemical and mechanical insults, for controlling pathophysiological processes of temperature control, sensation, inflammation, pigmentation, fibrosis, and wound healing [1].

A number of hormones and neuroendocrine factors are reportedly involved in the processes, such as catecholamines, acetylcholine, glutamate, serotonin, corticotropin-releasing hormone, urocortin, proopiomelanocortin-derived peptides, substance P, enkephalins, nitric oxide, neurotrophins, growth factors, steroids, vitamin D, and many others [1, 2]. In addition, the human skin expresses receptors for various hormones and neurotransmitters, including growth hormone/insulin-like growth factor-1, neuropeptides, sex steroids, glucocorticoids, retinoids and vitamin D, thyroid hormones, and so on [2]. Furthermore, these factors may be responsible for controlling skin aging and skin cancers [1, 3]. Through these findings and ideas, there has been an emerging concept that the skin is an endocrine organ [2].

Recently, there has been growing evidence that the skin could participate in blood pressure (BP) control, by controlling skin sodium accumulation as well as vasoconstriction. The first report was the finding that the increased accumulation of skin sodium is associated with BP elevation in humans by magnetic resonance imaging of sodium [4]. Subsequently, it has been shown that, despite renal water loss, BP is elevated by skin water conservation with vasoconstriction to suppress cutaneous water loss in spontaneously hypertensive rats [5].

The epidermis, representing the outmost layer of the skin, is predominantly formed by keratinocytes and is thought to control water loss from the skin (transepidermal water loss). Interestingly, the skin epidermal and dermal tissue, especially keratinocytes, express multiple hormones and hormone receptors [1, 2]. Moreover, the skin expresses most of the renin-angiotensin system (RAS) components, including angiotensinogen, renin, angiotensin-converting enzyme, angiotensin II (Ang II), and Ang II type 1 receptor (AT1R) [6]. It has become a consensus that, in addition to the systemic circulating RAS, the tissue RAS, e.g., the RAS in the renal, cardiac and vascular tissues, can regulate the local RAS activity, contributing to physiological and pathophysiological functions locally. However, the functional role of “the skin RAS” in BP control has been unclear and remained elusive.

In the latest issue of nature communications, Taguchi et al. reported the phenotypes of keratinocyte-specific deletion of Ang II receptor-associated protein (ATRAP) in mice in order to investigate the pathophysiological role of the skin RAS in BP control and the development of hypertension [7]. ATRAP has been cloned as a molecule that directly binds to the carboxy-terminal domain of AT1R and has been shown to promote the constitutive internalization of AT1R from the cell surface into the cytoplasm, resulting in suppression of AT1R signaling pathways locally [8]. In fact, enhanced tissue ATRAP expression suppresses the activation of tissue AT1R signaling, whereas decreased tissue ATRAP expression accelerates the tissue RAS activation and related damages, especially in the kidney [9, 10]. However, its role in the skin has remained unknown so far. In the current study, they clearly showed that the keratinocyte-specific deletion of ATRAP can significantly influence BP regulation and exacerbate Ang II-induced hypertension [7]. Furthermore, ATRAP knockout (KO) mice showed skin-specific increases in angiotensinogen and Ang II levels, while the keratinocyte-specific concomitant deletion of AT1R or the treatment with an AT1R blocker in KO mice cancelled these changes, demonstrating the pathogenic role of the activated local, not systemic, RAS of the skin in this hypertensive model [7]. As for its mechanisms, the urine volume was increased in KO mice while body fluid volume was comparable between the genotypes, suggesting decreased water loss from the skin in KO mice. They also found that temperature-induced skin vasodilation eliminated these changes, indicating the contribution of skin RAS-mediated vasoconstriction to limited transepidermal water loss and BP elevation (Fig. 1).

Fig. 1

The role of the skin RAS in the local regulation of capillary blood flow and cutaneous water conservation/loss. a A normal condition in the presence of ATRAP at a normal temperature, b a condition in the presence of ATRAP with the activated skin RAS at a low temperature, c a condition in the absence of ATRAP with the activated skin RAS at a low temperature, and d a condition in the absence of ATRAP with the activated skin RAS at a high temperature. RAS renin-angiotensin system, ATRAP angiotensin II receptor-associated protein, Ang II angiotensin II, AT1R angiotensin II type 1 receptor, BP blood pressure

These findings suggest the importance of skin RAS in the control of local blood flow and water conservation/loss in the skin, thereby contributing to BP regulation systemically. Although intriguing, further investigations are no doubt necessary to validate this hypothesis and expand this idea to a potential strategy for therapeutic interventions in hypertension in the future.