New findings in 2017 enhanced our understanding of the mechanisms that regulate blood pressure. Key studies provided insights into immune mechanisms, the role of the gut microbiota, the adverse effects of perivascular fat and inflammation on the vasculature, and the contribution of rare variants in renin–angiotensin–aldosterone system genes to salt sensitivity

Theyear 2017 saw the publication of many basic and clinical studies in the fieldof hypertension as well as new American Heart Association and American Collegeof Cardiology guidelines for the management of high blood pressure in adults1.Here, I focus on key studies that advanced understanding of basic mechanisms ofblood pressure regula-tion and vascular dysfunction, including three studiesthat provide new insights into the salt sensitivity of blood pressure.Researchinto immune mechanisms of hypertension has grown substantially in recent yearsand 2017 was no exception. As angio-tensin II (ANGII) infusion increases bloodpressure via a mechanism involving increased production of IL?17 from T helper17 (TH17)cells in mice2,and salt induces TH17cells via a serum and glucocorticoid-regulatedkinase 1 (SGK1)-dependent pathway3,Norlander et al. evaluated whether SGK1 signalling in T cellscontributes to salt-induced blood pressureelevation and end-organ damage4.They report that in mice, T cell-specificdele-tion of Sgk1 blunted blood pressure elevation and abrogatedendothelial dysfunction and renal injury in response to ANGII infusion.Deoxycorticosterone acetate–salt-inducedblood pressure elevation and vascular inflam-mation were also attenuated inthese mice. The basolateral Na /K /2Cl?cotransporter1 (NKCC1; also known as solute carrier family 12 member 2) was upregulated inCD4 Tcells cul-tured in TH17?polarizing conditions and medi-ated a salt-inducedincrease in the expression of SGK1 and the IL?23 receptor (which has a role inTH17cell differentiation). Thus, T cell SGK1 and NKCC1 are novel mediators of theeffectswasalso blunted in Tcrδ?/?mice. In a cohort ofpeople with or without coronary artery disease and/or hypertension, a multiplelin-ear regression model showed similar, additive correlations between TCRγ constant region expression in blood, age and sex; the addition ofcoronary artery disease to the model did not improve these correlations. Thus, γδT cells might contribute to the development of hypertension and area novel target for therapy. The incidence of aorticaneurysms is increased in patients with hypertension and atherosclerosiscompared with the general population. In 2017, increasing evidence for a roleof perivascular fat and inflamma-tion in vascular remodelling led to a study ofthe potential role of perivascular visceral adipose tissue (VAT) in aneurysmforma-tion. Sakaue et al.7 tested the hypothesis thatgenetic deletion of type 1a angiotensin II receptor (AGTR1A) in VAT could bluntthe development of aortic aneurysms in apolipoprotein E-deficient(Apoe?/?)mice. They found that, compared with transplantation of VAT from Apoe?/?mice,transplantation of VAT from Apoe?/?/Agtr1a?/?miceto around the abdominal aorta of Apoe?/?recipientsreducedtheformation of aortic aneurysms, infiltration of macrophages and gelatinolyticactivity in the abdominal aorta. In addition, AGTR1A activation polarized VATmacrophages to an inflammatory phenotype, and AGTR1A defi-ciency resulted in areduction in the expression of pro-inflammatoryosteopontin in VAT and in ANGII?induced osteopontin production by culturedadipose cells. Moreover, treat-ment with an osteopontin-neutralizinganti-body reduced ANGII?induced macrophage migration. Consistent with thesefindings, the researchers showed that transplantation of VAT from osteopontin-deficientApoe?/?micewas more effective in reducing formation of aortic aneurysms than wastransplantation of Apoe?/?VAT.They conclude that VAT AGTR1A has a role in the formation of abdominal aorticaneurysms via a mechanism involving osteopontin. These findings couldpotentially prompt use of inhibitors of the renin–angiotensinsystem to prevent the development or progression of aortic aneurysms in at?riskpatients, including those with hypertension. Finally,a discussion of recent advances in the understanding of hypertension would not becomplete without the inclusion of a genetic study. Genome-wideassociation studies (GWAS) and candidate gene studies have iden-tified commongenetic variants that influence the salt sensitivity of blood pressure,including numerous single-nucleotidepolymorphisms in renin–angiotensin–aldosteronesystem (RAAS) genes8. However, these common variants explain only asmall part of the heritability of blood pressure sensitivity to salt. In 2017,Kelly et al. conducted a resequencing study in which they evaluated theassociations of rare variants of seven RAAS genes with blood pressure saltsensitivity in the 300 most salt-sensitiveand 300 most salt-resistant participants of theGenSalt study9.The seven genes (RENBP, ACE2, AGTR1, HSD11B1, HSD11B2,NR3C2 and APLN) were selected based on their poten-tial roles inthe regulation of blood pressure. The researchers found that individuals withrare variants in these genes had 1.5?fold greater odds of being salt sensitivethan those without rare variants. In addition, the APLN gene wasassociated with salt sensitivity and rare APLN variants conferred 2.2?foldincreased odds of salt sensitivity. Analyses of 50 common and low-frequencyvariants identified associations between single markers of the remaining sixRAAS genes and salt-sensitive phenotypes. Afteradjustment for multiple testing, how-ever, only the RENBP variantrs78377269 was associated with salt sensitivity. Each copy of the minor alleleof this variant resulted in a 1.6 mmHg greater blood pressure response toincreased dietary sodium and was associated with a doubling of the odds of saltsensitiv-ity. This study provides the first evidence of a potential contributionof rare RAAS gene variants to the salt sensitivity of blood pressure.In summary, key studies published dur-ing 2017 open new vistasinto mechanisms of blood pressure elevation and aortic aneurysm formation thatbring together salt, immunity, genetics, the RAAS and the vasculature (FIG. 1).These advances provide opportunities for the discovery of novel biomarkers andtherapeutic targets for hypertension.

1. Whelton, P. K. et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension http://dx./10.1161/HYP.0000000000000065(2017); J. Am. Coll. Cardiol. http://dx./10.1016/j.jacc.2017.11.005 (2017).

2. Madhur, M. S. et al. Interleukin 17 promotes angiotensin II?induced hypertension and vascular

dysfunction. Hypertension 55, 500–507 (2010).

3. Wu, C. et al. Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature 496,

513–517 (2013).

4. Norlander, A. E. et al. A salt-sensing kinase in T lymphocytes, SGK1, drives hypertension and

hypertensive end-organ damage. JCI Insight 2, e92801(2017).

5. Wilck, N. et al. Salt-responsive gut commensal modulates TH17 axis and disease. Nature 551,585–589 (2017).

6. Caillon, A. et al. Gamma/delta T cells mediate angiotensin II?induced hypertension and vascular injury.

Circulation 135, 2155–2162 (2017).

7. Sakaue, T. et al. Perivascular adipose tissue angiotensin II type 1 receptor promotes vascular inflammation and aneurysm formation. Hypertension 70, 780–789(2017).

8. He, J. et al. Genome-wide association study identifies 8 novel loci associated with blood pressure responses to interventions in Han Chinese. Circ. Cardiovasc. Genet. 6,598–607 (2013).

9. Kelly, T. N. et al. Resequencing study identifies rare renin–angiotensin–aldosterone system variants

associated with blood pressure salt-sensitivity: the GenSalt study. Am. J. Hypertens. 30, 495–501 (2017).