LAUSR

The renin–angiotensin system (RAS) consists of angiotensinogen, renin, angiotensin-converting enzyme, angiotensin II (Ang II) and the Ang II type 1 (AT1) and type 2 (AT2) receptors [1]. RAS activities regulate blood pressure (BP), blood volume, cell proliferation and differentiation, metastasis, and tissue remodeling. Several new findings focused on topics including Ang 1–7, AT2/Mas, and AT4 insulin-regulated membrane aminopeptidase, several Ang II-generating enzymes, and AT1/AT2 heterodimerization have been reported over the past few decades. The sorting nexin 1 (SNX) family is composed of a diverse group of cytoplasmic and membrane-associated proteins that are involved in various aspects of receptor endocytosis and trafficking through endosomes [2–4]. Endocytosis and trafficking are also important functions of G protein-coupling receptors (GPCRs), including the AT1 and AT2 receptors. For example, while SNX1 binds two dopamine receptors (D1 and D5 receptors), which are GPCRs, it binds only the D5 receptor strongly [5, 6]. Recently, Snx1 mice were shown to have high BP associated with increased renal expression of the AT1 receptor, nicotinamide adenine dinucleotide phosphate oxidase subunits, D5 receptor, and sodium chloride cotransporter [7]. Acute renal-restricted depletion of SNX1 resulted in a blunted natriuretic response and high BP in mice due to impaired D5 receptor activity. In addition, several SNX1 SNPs were shown to be associated with an antihypertensive response to hydrochlorothiazide monotherapy among hypertensive African Americans in the Pharmacogenomic Evaluation of Antihypertensive Responses study. More recently, providing greater mechanistic precision, in this issue of Hypertension Research, Liu et al. successfully report that Ang II-induced contraction of mesenteric arteries was much greater in Snx1 mice than in WT mice, whereas there was no obvious difference in phenylephrine-induced contraction between the mice [8]. Interestingly, AT1 receptor protein levels in the aorta were significantly elevated in the Snx1 mice. In addition, the authors found that AT1 receptor protein levels, but not AT1 receptor mRNA levels, were elevated after SNX1 knockdown, probably independent of the D5 receptor, which indicated that SNX1 may be involved in the process of AT1 receptor protein degradation. This may represent a novel mechanism for the regulation of BP. Proteasomes and lysosomes are the two most important proteolytic machines in cells [9]. In this study, proteasomal inhibition, rather than lysosomal inhibition, increased AT1R expression in embryonic thoracic aortic smooth muscle cells [8]. Systemic administration of proteasome inhibitors suppressed pressure-overload cardiac hypertrophy and benefitted long-term cardiac remodeling in animal models [10]. On the other hand, a proteasome inhibitor promoted maladaptive remodeling in surviving mice with transverse aortic constriction and activated the calcineurin-nuclear factor of activated T cells pathway in cardiomyocytes in vitro and in vivo [11]. Thus, the cause of this conflict in the data is unclear at this time. Notably, there has been a wealth of discussion on the effects of proteasome inhibition on vascular function and remodeling, which reduce high BP [12]. Proteasomal functional insufficiency is a major pathogenic factor in the cardiovascular system. Finally, this study provides useful information due to the finding that SNX1mediated AT1 receptor degradation occurs mainly through the proteasomal pathway [8]. The Fig. 1 shows possible mechanisms for the interaction between the AT1 receptor and SNX1. Functional SNX1 initiates Ang II-mediated AT1 receptor activation at the plasma membrane, which results in dissociation of the G protein from the receptor and activates signal transduction (high blood pressure signaling), subsequently inducing receptor internalization and trafficking (Fig. 1A). Thus, * Shin-ichiro Miura [email protected]