Obesity is a potent predictor of cardiovascular disease and associated risk factors, including hypertension. Systemic inflammation has been suggested by a number of studies to be an important link between excess adiposity and hypertension, yet the majority of the studies have been conducted exclusively in males. This is problematic since women represent ∼53% of hypertensive cases and are more likely than men to be obese. There is a growing body of literature supporting a central role for immune cell activation in numerous experimental models of hypertension, and both the sex of the subject and the sex of the T cell have been shown to impact blood pressure (BP) responses to hypertensive stimuli. Moreover, sex steroid hormones play an important role in energy homeostasis, as well as in the regulation of immune responses; estrogen, in particular, has a well-known impact on both cardiovascular and metabolic disorders. Therefore, the purpose of this review is to examine whether sex or sex hormones regulate the role of the immune system in the development of hypertension and related vascular dysfunction in response to metabolic changes and stimuli, including a high-fat diet.

Evidence supports a sex difference in the impact of a high-fat diet (HFD) on cardiovascular outcomes, with male experimental animals exhibiting greater increases in blood pressure (BP) than female experimental animals. The immune system has been implicated in HFD-induced increases in BP, and there is a sex difference in T-cell activation in hypertension. The goal of this study was to determine the impact of HFD on BP and aortic and renal T cell profiles in male and female Dahl salt-sensitive (DSS) rats. We hypothesized that male DSS rats would have greater increases in BP and T cell infiltration in response to a HFD compared with female DSS rats. BP was measured by tail-cuff plethysmography, and aortic and renal T cells were assessed by flow cytometric analysis in male and female DSS rats on a normal-fat diet (NFD) or HFD from 12 to 16 wk of age. Four weeks of HFD increased BP in male and female DSS rats to a similar degree. Increases in BP were accompanied by increased percentages of CD4+ T cells and T helper (Th)17 cells in both sexes, although male rats had more proinflammatory T cells. Percentages of renal CD3+ and CD4+ T cells as well as Th17 cells were increased in both sexes by the HFD, although the increase in CD3+ T cells was greater in male rats. HFD also decreased the percentage of aortic and renal regulatory T cells in both sexes, although female rats maintained more regulatory T cells than male rats regardless of diet. In conclusion, both male and female DSS rats exhibit BP sensitivity to a HFD; however, the mechanisms mediating HFD-induced increases in BP may be distinct as male rats exhibit greater increases in the percentage of proinflammatory T cells than female rats.NEW & NOTEWORTHY Our study demonstrates that male and female Dahl salt-sensitive rats exhibit similar increases in blood pressure to a high-fat diet and an increase in aortic and renal T cells. These results are in contrast to studies showing that female rats remain normotensive and/or upregulate regulatory T cells in response to hypertensive stimuli compared with male rats. Our data suggest that a 4-wk high-fat diet has sex-specific effects on the T cell profile in Dahl salt-sensitive rats.

Obesity is a common metabolic disorder that has become a widespread epidemic in several countries. Sex and gender disparities in the prevalence of cardiovascular disease (CVD) have been well documented with premenopausal women having a lower incidence of CVD than age-matched men. However, women are more likely than men to suffer from obesity, which can predispose them to a greater risk of CVD. The mechanisms underlying high-fat diet (HFD)-or obesity-induced hypertension are not well defined, although immune system activation and inflammation have been implicated in several studies. Further, the sex of the subject can have a profound influence on the immune response to hypertensive stimuli. Therefore, the purpose of this review is to examine the effects of sex and gender on the role of the immune system in HFD-induced hypertension and vascular dysfunction.

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Immune cell infiltration into the kidney has been suggested to occur in response to renal injury but may also contribute to the development of hypertension in the Dahl salt‐sensitive (SS) rat model, initiating a feed‐forward cascade of progressive hypertension, hypertension induced kidney injury, and immune cell infiltration. Experimentally, it has been difficult to separate these factors, given the normally close relationship between blood pressure and renal injury in this model. We have recently reported that HCO3− supplementation limits the development of tubular casts and fibrosis in the kidneys of high salt fed Dahl SS rats, independent of lowering systemic arterial pressure. Therefore, in the current study we leveraged this phenotype to better delineate the roles of hypertension and renal tubular injury/fibrosis on the renal immune cell profile.11 week old Dahl SS rats were either treated with vehicle (0.1M NaCl; n=5) or NaHCO3−(0.1M; n=5) in drinking water for the length of the study. At the beginning of the study, rats were maintained on a 0.4% NaCl diet (Dyets AIN76A) for 4 days before being switched to an 8% NaCl diet for 14 days. On day 14 of 8% NaCl feeding, rats were anesthetized, arterial blood gas measurements taken and both arterial blood and the left kidney excised for flow cytometry analysis. Data are presented in the table below.Results and ConclusionsBicarbonate treatment markedly reduced tubular injury and fibrosis accompanied with significantly higher levels of M2 macrophages and a significantly lower levels of M1 macrophages, without altering renal T‐cell infiltration or blood pressure. Thus, our data for the first time suggest that the potential therapeutic effect of bicarbonate treatment might be mediated by induction of a phenotypic change of pro‐inflammatory M1 macrophage to tissue reparative M2 macrophage in Dahl salt‐sensitive ratsSupport or Funding InformationThis work was supported by NIH NIDDK grant 5R01DK099548 KIDNEY CD3+ CD4+(% CD3) CD44+(% CD3) CD69+ (% CD3) FOXP3+ (% CD3) M1 M2 Vehicle (n=5) 1.44±0.23 55.2±1.6 59±2 0.6±0.1 1.1±0.2 0.30±0.03 0.16±0.04 Bicarbonate (n=5) 1.44±0.39 51.4±3.1 52±3 0.8±0.2 1.8±0.4 0.14±0.02 0.3±0.03 p (t‐test) 0.4 0.3 0.08 0.44 0.17 0.004** 0.03* BLOOD Vehicle (n=4) 54±1.2 55±1.9 19±2.2 1.2±0.3 2.5±0.3 Bicarbonate (n=5) 57.4±2 52.6±1.4 14.2±1.9 0.9±0.3 4.4±0.5 p (t‐test) 0.22 0.33 0.14 0.45 0.02*