◂Fig.1 Introduction
Hypertension is the leading cause of cardiovascular disease and one of the major causes of premature death world wide [30]. Its development is influenced by several fac tors, including genetic background, obesity, and excess salt intake [34] ranging from 8 to 10 g daily [2]. Salt-sensitive hypertension is a common type of high blood pressure that is exacerbated by a high-salt diet and affects approximately 30% of healthy humans [2] and 50% of individuals with hypertension [41]. Several pathways adjust salt excretion to match changes in dietary salt intake in the kidney. Gitelman patients show renal salt wasting due to inactivating muta tions of the SLC12A3 gene encoding the thiazide-sensi tive sodium chloride co-transporter NCC, whereas Liddle patients retain renal sodium due to mutation in the SCNN1β and SCNN1γ genes encoding the b- and g-subunit of ENaC [3, 37]. Furthermore, an implication of the vascular, the sympathetic nervous, the gastrointestinal, and the immune system and the skin was demonstrated as well [10]. Evi dence of the heritability of salt sensitivity was documented, and allelic variants of candidate genes not only affect the renal sodium transport like the angiotensin II type 1 recep tor, the 11β-hydroxysteroid dehydrogenase (11βHSD), or the chloride voltage-gated channel Ka (CLCNKA) but also vascular reactivity like the solute carrier family 24 member 3 (SLC24A3) or the endothelin receptor type B (ENDRB) (for review, see [32]). Several rodent models were used to study salt-sensitive hypertension like Dahl salt-sensitive rats, DOCA-salt-induced mice, or genetically engineered mice mutant for the 11βHSD2 or the βENaC subunit genes (for review, see [7, 32]). Additionally, sex-specific salt sensitiv ity was reported following high-salt diet in female Balb/c mice resulting in impaired endothelium-dependent vasodilation [12] and in male C57Bl/6J mice exhibiting sympathetic overactivity without renal sodium retention [47]. Following norepinephrine or isoproterenol treatment, C57Bl/6J mice exhibited NCC-mediated sodium retention and salt-sensi tive hypertension. In these mice, increased glucocorticoid receptor binding was due to b-adrenergic receptor stimula tion suggesting a role for the development of salt-induced hypertension [36]. There is increasing evidence that GR signaling is involved in salt-sensitive hypertension. Glucocorticoid excess in Cushing syndrome or glucocorticoid resist ance in certain GR mutations induced hypertension and affected renal sodium retention [21]. Approximately 50% of patients with hypercorticolism and GR muta tions exhibit hypertension (for review, see [55]). When kept on a high-salt diet, mice with reduced GR expres sion showed salt sensitivity and sustained hypertension that was attributed to increased mineralocorticoid recep tor activation [24]. Similarly, rats with a mutation within the second zinc finger domain of the GR (Fig. 1A; GR+/ em2 [52]) exhibited higher plasma corticosterone levels although salt-sensitive hypertension was only provoked in combination with high salt intake. These rats carried an out-of-frame mutation of the DNA-binding domain of the GR that resulted in an early Stop codon (GR+/em2) and thus represents a null allele (Figure S1A, B [52];). It has been furthermore reported that high salt intake activated the HPA axis, amplified the stress response, and altered glucocorticoid responsiveness in mice [6] indicating an interplay between salt intake, plasma cortisol/corticoster one, and tissue sensitivity to glucocorticoids. Excess glucocorticoids stimulate renal sodium trans port and can thus mediate mineralocorticoid-like effects although both receptors have distinct but also overlapping physiological functions (for review, see [55]). A recent study proposed that the GR is required for efficient aldoster one-induced transcription via the mineralocorticoid recep tor [25, 59]. In line with these results, it has been dem onstrated that mice with reduced global expression of GR (GR βgeo/+) exhibit glucocorticoid resistance with increased plasma corticosterone levels and high-salt-induced hyper tension, suggesting adaptive failure of the renal vasculature and tubules [24]. To decipher the role of renal GR in salt sensitive hypertension, a nephron tubule-specific mouse GR knockout was generated that overall maintained the Na+ and K+ balance independent of the salt diet [4]. These mice did not present hypercorticosteronemia, and on a high-salt diet, their systolic blood pressure was not different from that of the controls, although these mutant mice showed a significant increase in diastolic blood pressure. This find ing suggested that circulating plasma corticosteroids are involved in sodium homeostasis [4].
