Functional NADPH oxidase 2 in T cells amplifies salt-sensitive hypertension and associated renal damage.

Infiltrating T cells in the kidney amplify salt-sensitive (SS) hypertension and renal damage, but the mechanisms are not known. Genetic deletion of T cells (SSCD247-/-) or of the p67phox subunit of NADPH oxidase 2 (NOX2; SSp67phox-/-) attenuates SS hypertension in the Dahl SS rat. We hypothesized that reactive oxygen species produced by NOX2 in T cells drive the SS phenotype and renal damage. T cells were reconstituted by adoptively transferring splenocytes (∼10 million) from the Dahl SS (SS→CD247) rat, the SSp67phox-/- rat (p67phox→CD247), or only PBS (PBS→CD247) into the SSCD247-/- rat on postnatal day 5. Animals were instrumented with radiotelemeters and studied at 8 wk of age. There were no detectable differences in mean arterial pressure (MAP) or albuminuria between groups when rats were maintained on a low-salt (0.4% NaCl) diet. After 21 days of high-salt diet (4.0% NaCl), MAP and albuminuria were significantly greater in SS→CD247 rats compared with p67phox→CD247 and PBS→CD247 rats. Interestingly, there was no difference between p67phox→CD247 and PBS→CD247 rats in albuminuria or MAP after 21 days. The lack of CD3+ cells in PBS→CD247 rats and the presence of CD3+ cells in rats that received the T cell transfer demonstrated the effectiveness of the adoptive transfer. No differences in the number of CD3+, CD4+, or CD8+ cells were observed in the kidneys of SS→CD247 and p67phox→CD247 rats. These results indicate that reactive oxygen species produced by NOX2 in T cells participates in the amplification of SS hypertension and renal damage.NEW & NOTEWORTHY Our current work used the adoptive transfer of T cells that lack functional NADPH oxidase 2 into a genetically T cell-deficient Dahl salt-sensitive (SS) rat model. The results demonstrated that reactive oxygen species produced by NADPH oxidase 2 in T cells participate in the amplification of SS hypertension and associated renal damage and identifies a potential mechanism that exacerbates the salt-sensitive phenotype.

Impact of bedding on Dahl salt-sensitive hypertension and renal damage.

Salt-sensitive hypertension, increases in blood pressure in response to increased salt intake, is associated with an increased risk of morbidity, mortality, and end-organ damage compared with salt-resistant hypertension. The Dahl salt-sensitive (SS) rat mimics the phenotypic characteristics observed in human hypertension when rats are challenged with a high-salt diet. Our previous work demonstrated that environmental factors, such as dietary protein, alter the severity of salt sensitivity in Dahl SS rats and should be an important consideration in experimental design. The present study investigated how the bedding on which animals were maintained (wood vs. corncob) could impact the SS phenotype in the Dahl SS rat. Animals that were maintained on corncob bedding exhibited a significant attenuation in blood pressure and renal end-organ damage in response to a high-salt diet compared with animals maintained on wood bedding. This attenuation was associated with an improvement in renal function and reduction in immune cell infiltration into the kidneys of Dahl SS rats maintained on corncob bedding. These results indicate that the type of bedding impacts the SS phenotype in the Dahl SS rat and that the bedding used in experiments can be a confounding factor to consider during data interpretation and experimental design.NEW & NOTEWORTHY Results from our present study demonstrate the profound effect of animal bedding on the severity of salt-sensitive hypertension, renal damage, and inflammation in Dahl salt-sensitive rats. This study highlights the important consideration that should be given to environmental factors, namely, the type of bedding in animal facilities, in experimental design and data interpretation.

CCL2 mediates early renal leukocyte infiltration during salt-sensitive hypertension.

Studies examining mechanisms of Dahl salt-sensitive (SS) hypertension have implicated the infiltration of leukocytes in the kidneys, which contribute to renal disease and elevated blood pressure. However, the signaling pathways by which leukocytes traffic to the kidneys remain poorly understood. The present study nominated a signaling pathway by analyzing a kidney RNA sequencing data set from SS rats fed either a low-salt (0.4% NaCl) diet or a high-salt (4.0% NaCl) diet. From this analysis, chemokine (C-C motif) ligand 2 (CCL2) and chemokine (C-C motif) receptor 2 (CCR2) were nominated as a potential pathway modifying renal leukocyte infiltration and contributing to SS hypertension. The functional role of the CCL2/CCR2 pathway was tested by daily administration of CCR2 antagonist (RS-102895 at 5 mg·kg-1·day-1 in DMSO) or DMSO vehicle for 3 or 21 days by intraperitoneal injections during the high salt challenge. Blood pressure, renal leukocyte infiltration, and renal damage were evaluated. The results demonstrated that RS-102895 treatment ameliorated renal damage (urinary albumin excretion; 43.4 ± 5.1 vs. 114.7 ± 15.2 mg/day in vehicle, P < 0.001) and hypertension (144.3 ± 2.2 vs. 158.9 ± 4.8 mmHg in vehicle, P < 0.001) after 21 days of high-salt diet. It was determined that renal leukocyte infiltration was blunted by day 3 of the high-salt diet (1.4 ± 0.1 vs. 1.9 ± 0.2 in vehicle × 106 CD45+ cells/kidney, P = 0.034). An in vitro chemotaxis assay validated the effect of RS-102895 on leukocyte chemotaxis toward CCL2. The results suggest that increased CCL2 in SS kidneys is important in the early recruitment of leukocytes, and blockade of this recruitment by administering RS-102895 subsequently blunted the renal damage and hypertension.

Influences of environmental factors during preeclampsia.

Preeclampsia is a pregnancy-specific disorder that impacts 5-8% of pregnancies and has long-term cardiovascular and metabolic implications for both mother and fetus. The mechanisms are unclear; however, it is believed that preeclampsia is characterized by abnormal vascularization during placentation resulting in the manifestation of clinical signs such as hypertension, proteinuria, and endothelial dysfunction. Although there is no current cure to alleviate the clinical signs, an emerging area of interest in the field is the influence of environmental factors including diet on the risk of preeclampsia. Because preeclampsia has serious cardiovascular implications to both the mother and fetus and most antihypertensive medications are contraindicated in pregnancy, it is important to investigate other potential therapeutic options such as dietary manipulation. The emerging field of nutrigenomics links diet with the gene expression of known pathways such as oxidative stress and inflammation via microbiome-mediated metabolites and could serve as one potential avenue of therapeutic targets for preeclampsia. Although the exact role of nutrition in the pathogenesis of preeclampsia is unknown, this review will focus on known pathways involved in the development of preeclampsia and how dietary intake modulates the microbiome, oxidative stress, and inflammation with an emphasis on nutrigenomics as a potential avenue of further investigation to better understand this pathology.

Splenocyte transfer exacerbates salt-sensitive hypertension in rats.

NEW FINDINGS: What is the central question of this study? Recruitment of immune cells to the kidney potentiates hypertensive pathology, but more refined methods are needed to assess these cells functionally. Adoptive transfer studies of immune cells have been limited in rat models and especially in the study of salt-sensitive hypertension. We tested the hypothesis that splenocyte transfer into T-cell-deficient rats is sufficient to exacerbate salt-sensitive hypertension. What is the main finding and its importance? We demonstrate that transfer of splenocytes into T-cell-deficient animals exacerbates salt-sensitive hypertension, and an enrichment in the CD4+ compartment specifically induces this phenomenon. ABSTRACT: Increasing evidence of immune system activation during the progression of hypertension and renal injury has led to a need for new methods to study individual cell types. Transfer of immune cells serves as a powerful tool to isolate effects of specific subsets. Transfer studies in Rag1-/- mice have demonstrated an important role of T-cell activation in hypertension, but this approach has yielded limited success in rat models. Using the T-cell-deficient Dahl salt-sensitive (SS) rat, SSCD247-/- , we hypothesized that splenocyte transfer from SS wild-type animals into SSCD247-/- animals would populate the T-cell compartment. The Dahl SS background provides a model for studying salt-sensitive hypertension; therefore, we also tested whether the dietary salt content of the donor would confer differential salt sensitivity in the recipient. To test this, donors were maintained on either a low-salt or a high-salt diet, and at postnatal day 5 the recipients received splenocyte transfer from one of these groups before a high-salt diet challenge. We showed that splenocyte transfer elevated blood pressures while rats were fed low salt and exacerbated the salt-sensitive increase in pressure when they were fed fed high salt. Furthermore, transfer of splenocytes conferred exacerbated renal damage. Lastly, we confirmed the presence of T cells in the circulation and in the spleen, and that infiltration of immune cells, including T cells, macrophages and B cells, into the kidney was elevated in those receiving the transfer. Interestingly, the source of the splenocytes, from donors fed either a low-salt or a high-salt diet, did not significantly affect these salt-sensitive phenotypes.

Dietary Protein: Mechanisms Influencing Hypertension and Renal Disease.

PURPOSE OF REVIEW: This review will provide an in-depth coverage of the epidemiological and pre-clinical literature surrounding the role of dietary protein in hypertension, with a special emphasis on the history of our work on the Dahl salt-sensitive rat. RECENT FINDINGS: Our studies have dedicated much effort into understanding the relationship between dietary protein and its effect on the development of salt-sensitive hypertension and renal injury. Our evidence over the last 15 years have demonstrated that both the source and amount of dietary protein can influence the severity of disease, where we have determined mechanisms related to immunity, the maternal environment during pregnancy, and more recently the gut microbiota, which significantly contribute to these diet-induced effects. Deeper understanding of these dietary protein-related mechanisms may provide insight on the plausibility of dietary modifications as future therapeutic avenues for hypertension and renal disease.

Salt-sensitive increase in macrophages in the kidneys of Dahl SS rats.

Studies of Dahl salt-sensitive (SS) rats have shown that renal CD3+ T cells and ED-1+ macrophages are involved in the development of salt-sensitive hypertension and renal damage. The present study demonstrated that the increase in renal immune cells, which accompanies renal hypertrophy and albuminuria in high-salt diet-fed Dahl SS rats, is absent in Sprague-Dawley and SSBN13 rats that are protected from the SS disease phenotype. Flow cytometric analysis demonstrated that >70% of the immune cells in the SS kidney are M1 macrophages. PCR profiling of renal myeloid cells showed a salt-induced upregulation in 9 of 84 genes related to Toll-like receptor signaling, with notable upregulation of the Toll-like receptor 4/CD14/MD2 complex. Because of the prominent increase in macrophages in the SS kidney, we used liposome-encapsulated clodronate (Clod) to deplete macrophages and assess their contribution to salt-sensitive hypertension and renal damage. Dahl SS animals were administered either Clod-containing liposomes (Clod-Lipo), Clod, or PBS-containing liposomes as a vehicle control. Clod-Lipo treatment depleted circulating and splenic macrophages by ∼50%; however, contrary to our hypothesis, Clod-Lipo-treated animals developed an exacerbated salt-sensitive response with respect to blood pressure and albuminuria, which was accompanied by increased renal T and B cells. Interestingly, those treated with Clod also demonstrated an exacerbated phenotype, but it was less severe than Clod-Lipo-treated animals and independent of changes to the number of renal immune cells. Here, we have shown that renal macrophages in Dahl SS animals sustain a M1 proinflammatory phenotype in response to increased dietary salt and highlighted potential adverse effects of Clod-Lipo macrophage depletion.

Renal nerves and leukocyte infiltration in the kidney during salt-sensitive hypertension.

Based on previous studies suggesting a role of renal nerves in renal inflammation, the present studies were performed to test the hypothesis that renal nerves mediate renal damage in Dahl salt-sensitive (SS) hypertension by increasing renal leukocyte infiltration. Experiments were performed in Dahl SS rats with bilateral renal denervation (RDN) and bilateral sham operation (n = 10 or 11 per group) and with unilateral RDN and contralateral sham operation (n = 10). After denervation, rats were switched from a low-salt 0.4% NaCl (LS) diet to a high-salt 4% NaCl (HS) diet and maintained on HS diet for 21 days. Bilateral RDN reduced the magnitude of hypertension assessed by radiotelemetry in Dahl SS rats compared with sham-operated rats (mean arterial pressure 140.9 ±4.8 mmHg and 159.7 ± 3.5 mmHg, respectively) and reduced proteinuria at day 21 of HS diet. However, assessment of renal leukocyte infiltration demonstrated no significant effect of bilateral RDN on the number of infiltrating leukocytes (RDN 3.6 ± 0.5 × 106 vs. sham operated 4.3 ± 0.3 × 106 CD45+ cells) or any of the subsets examined by flow cytometry. The unilateral RDN experiment showed no effect of RDN on the renal infiltration of leukocytes (RDN 6.5 ± 0.9 × 106 vs. sham operated 6.1 ± 1.1 × 106 CD45+ cells/kidney) or renal damage in RDN vs. sham-operated kidney after 21 days of HS diet. This work investigated the relationship between renal nerves and renal inflammation during Dahl SS hypertension. Contrary to our hypothesis, the results of this work suggest that immune cell infiltration in the kidney of Dahl SS rats is not mediated by the renal nerves.

Rag1-null Dahl SS rats reveal that adaptive immune mechanisms exacerbate high protein-induced hypertension and renal injury.

The present study, performed in Dahl salt-sensitive (SS) and SS- Rag1-/- rats lacking T and B lymphocytes, tested the hypothesis that immune cells amplify salt-sensitive hypertension and kidney damage in response to a high-protein diet. After being weaned, SS and SS- Rag1-/- rats were placed on an isocaloric, 0.4% NaCl diet containing normal (18%) or high (30%) protein. At 9 wk of age, rats were switched to a 4.0% NaCl diet containing the same amount of dietary protein and maintained on the high-salt diet for 3 wk. After being fed the high-salt diet, SS rats fed high protein had amplified hypertension and albumin excretion (158.7 ± 2.6 mmHg and 140.8 ± 16.0 mg/day, respectively, means ± SE) compared with SS rats fed normal protein (139.4 ± 3.6 mmHg and 69.4 ± 11.3 mg/day). When compared with the SS rats, SS- Rag1-/- rats fed high protein were protected from exacerbated hypertension and albuminuria (142.9 ± 5.8 mmHg and 66.2 ± 10.8 mg/day). After 3 wk of the high-salt diet, there was a corresponding increase in total leukocyte infiltration (CD45+) in the kidneys of both strains fed high-protein diet. The SS- Rag1-/- rats fed high-protein diet had 74-86% fewer CD3+ T lymphocytes and CD45R+ B lymphocytes infiltrating the kidney versus SS rats, but there was no difference in the infiltration of CD11b/c+ monocytes and macrophages, suggesting that the protective effects observed in the SS- Rag1-/- rats are specific to the reduction of lymphocytes. With the SS- Rag1-/- rats utilized as a novel tool to explore the effects of lymphocyte deficiency, these results provide evidence that adaptive immune mechanisms contribute to the exacerbation of salt-induced hypertension and renal injury mediated by increased dietary protein intake.

Novel adaptive and innate immunity targets in hypertension.

Hypertension is a worldwide epidemic and global health concern as it is a major risk factor for the development of cardiovascular diseases. A relationship between the immune system and its contributing role to the pathogenesis of hypertension has been long established, but substantial advancements within the last few years have dissected specific causal molecular mechanisms. This review will briefly examine these recent studies exploring the involvement of either innate or adaptive immunity pathways. Such pathways to be discussed include innate immunity factors such as antigen presenting cells and pattern recognition receptors, adaptive immune elements including T and B lymphocytes, and more specifically, the emerging role of T regulatory cells, as well as the potential of cytokines and chemokines to serve as signaling messengers connecting innate and adaptive immunity. Together, we summarize these studies to provide new perspective for what will hopefully lead to more targeted approaches to manipulate the immune system as hypertensive therapy.

Intrauterine growth restriction programs an accelerated age-related increase in cardiovascular risk in male offspring.

Placental insufficiency programs an increase in blood pressure associated with a twofold increase in serum testosterone in male growth-restricted offspring at 4 mo of age. Population studies indicate that the inverse relationship between birth weight and blood pressure is amplified with age. Thus, we tested the hypothesis that intrauterine growth restriction programs an age-related increase in blood pressure in male offspring. Growth-restricted offspring retained a significantly higher blood pressure at 12 but not at 18 mo of age compared with age-matched controls. Blood pressure was significantly increased in control offspring at 18 mo of age relative to control counterparts at 12 mo; however, blood pressure was not increased in growth-restricted at 18 mo relative to growth-restricted counterparts at 12 mo. Serum testosterone levels were not elevated in growth-restricted offspring relative to control at 12 mo of age. Thus, male growth-restricted offspring no longer exhibited a positive association between blood pressure and testosterone at 12 mo of age. Unlike hypertension in male growth-restricted offspring at 4 mo of age, inhibition of the renin-angiotensin system with enalapril (250 mg/l for 2 wk) did not abolish the difference in blood pressure in growth-restricted offspring relative to control counterparts at 12 mo of age. Therefore, these data suggest that intrauterine growth restriction programs an accelerated age-related increase in blood pressure in growth-restricted offspring. Furthermore, this study suggests that the etiology of increased blood pressure in male growth-restricted offspring at 12 mo of age differs from that at 4 mo of age.

Gender differences in developmental programming of cardiovascular diseases.

Hypertension is a risk factor for cardiovascular disease, the leading cause of death worldwide. Although multiple factors contribute to the pathogenesis of hypertension, studies by Dr David Barker reporting an inverse relationship between birth weight and blood pressure led to the hypothesis that slow growth during fetal life increased blood pressure and the risk for cardiovascular disease in later life. It is now recognized that growth during infancy and childhood, in addition to exposure to adverse influences during fetal life, contributes to the developmental programming of increased cardiovascular risk. Numerous epidemiological studies support the link between influences during early life and later cardiovascular health; experimental models provide proof of principle and indicate that numerous mechanisms contribute to the developmental origins of chronic disease. Sex has an impact on the severity of cardiovascular risk in experimental models of developmental insult. Yet, few studies examine the influence of sex on blood pressure and cardiovascular health in low-birth weight men and women. Fewer still assess the impact of ageing on sex differences in programmed cardiovascular risk. Thus, the aim of the present review is to highlight current data about sex differences in the developmental programming of blood pressure and cardiovascular disease.

Glucose intolerance develops prior to increased adiposity and accelerated cessation of estrous cyclicity in female growth-restricted rats.

BACKGROUND: The incidence of metabolic disease increases in early menopause. Low birth weight influences the age at menopause. Thus, this study tested the hypothesis that intrauterine growth restriction programs early reproductive aging and impaired glucose homeostasis in female rats. METHODS: Estrous cyclicity, body composition, and glucose homeostasis were determined in female control and growth-restricted rats at 6 and 12 mo of age; sex steroids at 12 mo. RESULTS: Glucose intolerance was present at 6 mo of age prior to cessation of estrous cyclicity and increased adiposity in female growth-restricted rats. However, female growth-restricted rats exhibited persistent estrus and a significant increase in adiposity, fasting glucose, and testosterone at 12 mo of age (P < 0.05). Insulin release in response to a glucose challenge was blunted in conjunction with a reduction in protein expression of pancreatic glucose transporter type 2 and estrogen receptor-α at 12 mo of age in female growth-restricted rats (P < 0.05). CONCLUSION: This study demonstrated that slow fetal growth programmed glucose intolerance that developed prior to early estrous acyclicity; yet, fasting glucose levels were elevated in conjunction with increased adiposity, accelerated cessation of estrous cyclicity and a shift toward testosterone excess at 12 mo of age in female growth-restricted rats.

Sex differences in the developmental origins of cardiovascular disease.

The Developmental Origins of Health and Disease (DOHaD) proposes that adverse events during early life program an increased risk for cardiovascular disease. Experimental models provide proof of concept but also indicate that insults during early life program sex differences in adult blood pressure and cardiovascular risk. This review will highlight the potential mechanisms that contribute to the etiology of sex differences in the developmental programming of cardiovascular disease.

Sex-Dependency of T Cell-Induced Salt-Sensitive Hypertension and Kidney Damage.

BACKGROUND: It is established that the immune system, namely T cells, plays a role in the development of hypertension and renal damage in male Dahl salt-sensitive (SS) rats, but far less is known about this relationship in females. Rats with genetically deleted T cells via CD247 gene mutation on the Dahl SS background (SSCD247-/-) were utilized to interrogate the effect of sex and T cells on salt sensitivity. METHODS: We assessed the hypertensive and kidney injury phenotypes in male versus female SS and SSCD247-/- rats challenged with 3 weeks of high salt (4.0% NaCl). Differences in T cell activation genes were examined in renal T cells from male and female SS rats, and a sex-specific adoptive transfer was performed by injecting male or female splenocytes into either male or female SSCD247-/- recipients to determine the potential contribution of T cell sex. RESULTS: The lack of functional T cells in SSCD247-/- rats significantly reduced salt-induced hypertension and proteinuria in both sexes, although SSCD247-/- females exhibited greater protection from kidney damage. Adoptive transfer of either Dahl SS male or female splenocytes into SSCD247-/- male recipients exacerbated hypertension and proteinuria compared with controls, while in SSCD247-/- female recipients, exacerbation of disease occurred only upon transfer of male, but not female, SS splenocytes. CONCLUSIONS: The absence of T cells in the SSCD247-/- normalized sex differences in blood pressure, though sex differences in renal damage persisted. Splenocyte transfer experiments demonstrated that salt sensitivity is amplified if the sex of the T cell or the recipient is male.

Intact NOX2 in T Cells Mediates Pregnancy-Induced Renal Damage in Dahl SS Rats.

BACKGROUND: Hypertensive disorders of pregnancy are associated with increased risk for cardiovascular disease, renal disease, and mortality. While the exact mechanisms remain unclear, T cells and reactive oxygen species have been implicated in its pathogenesis. We utilized Dahl salt-sensitive (SS), SSCD247-/- (Dahl SS CD247 knockout rat; lacking T cells), and SSp67phox-/- (Dahl SS p67phox [NOX2 (NADPH [nitcotinamide adenine dinucleotide phosphate] oxidase 2)] knockout rat; lacking NOX2) rats to investigate these mechanisms in primigravida and multigravida states. METHODS: We assessed blood pressure and renal damage phenotypes in SS, SSCD247-/-, and SSp67phox-/- rats during primigravida and multigravida states. To investigate the contribution of NOX2 in T cells, we performed adoptive transfers of splenocytes or cluster of differentiation (CD)4+ T cells from either SS or SSp67phox-/- donors into SSCD247-/- recipients to determine pregnancy-specific alterations in phenotype. RESULTS: Multigravida SS rats developed significant pregnancy-induced renal damage and renal functional impairment associated with elevated maternal mortality rates, whereas deletion of T cells or NOX2 garnered protection. During primigravida states, this attenuation in renal damage was observed, with the greatest protection in the SSp67phox-/- rat. To demonstrate that NOX2 in T cells contributes to adverse pregnancy phenotypes, adoptive transfer of SS splenocytes into SSCD247-/- rats resulted in significant pregnancy-induced renal damage, whereas transfer of SSp67phox-/- splenocytes garnered protection. Specifically, the transfer of SS CD4+ T cells resulted in pregnancy-induced proteinuria and increases in uterine artery resistance index, an effect not seen with the transfer of SSp67phox-/- CD4+ T cells. CONCLUSIONS: T cells and NOX2-derived reactive oxygen species, thus, contribute to end-organ damage in both primigravida and multigravida pregnancies in the SS rat leading to increases in maternal mortality.

Microbiota-associated mechanisms underlying sexual dimorphism in hypertension.

Consistent research over the last 20 years has shown that there are clear sex differences in the pathogenesis of hypertension, the leading risk factor for the development of cardiovascular diseases. More recently, there is evidence in both humans and experimental animal models that causally implicates the gut microbiota in hypertension. It therefore follows that sex differences in the gut microbiota may mediate the extent of disease between sexes. This new field is rapidly changing and advancing, and the purpose of this review is to cover the most up-to-date evidence regarding the sexual dimorphism of the gut microbiota and its potential influence on the differential manifestation of hypertension in males versus females. Emphasis will be placed on the mechanisms thought to contribute to these sex differences in both the gut microbiota and hypertension, including sex steroid hormones, gut-derived metabolites, the immune system, and pregnancy.

Dietary Protein, Chronic Salt-Sensitive Hypertension, and Kidney Damage.

It has been estimated that over a fifth of deaths worldwide can be attributed to dietary risk factors. A particularly serious condition is salt-sensitive (SS) hypertension and renal damage, participants of which demonstrate increased morbidity and mortality. Notably, a large amount of evidence from humans and animals has demonstrated that other components of the diet can also modulate hypertension and associated end-organ damage. Evidence presented in this review provides support for the view that immunity and inflammation serve to amplify the development of SS hypertension and leads to malignant disease accompanied by tissue damage. Interestingly, SS hypertension is modulated by changes in dietary protein intake, which also influences immune mechanisms. Together, the evidence presented in this review from animal and human studies indicates that changes in dietary protein source have profound effects on the gut microbiota, microbiota-derived metabolites, gene expression, immune cell activation, the production of cytokines and other factors, and the development of SS hypertension and kidney damage.

Gut-Immune-Kidney Axis: Influence of Dietary Protein in Salt-Sensitive Hypertension.

Humans with salt-sensitive hypertension demonstrate increased morbidity, increased mortality, and renal end-organ damage when compared with normotensive subjects or those with salt-resistant hypertension. Substantial evidence from humans and animals has also demonstrated the role of dietary components other than salt to modulate hypertension. Evidence presented in this review provides support for the view that immunity and inflammation serve to amplify the development of salt-sensitive hypertension and leads to malignant disease accompanied by end-organ damage. Interestingly, salt-sensitive disease is modulated by changes in dietary protein intake, which also influences immune mechanisms. Together, the evidence presented in this review from animal and human studies indicates that changes in dietary protein source have profound effects on the gut microbiota, microbiota-derived metabolites, DNA methylation, gene expression, immune cell activation, the production of cytokines and other factors, and the development of salt-sensitive hypertension and related disease phenotypes.

Hypersensitivity to acute ANG II in female growth-restricted offspring is exacerbated by ovariectomy.

Female growth-restricted offspring are normotensive in adulthood. However, ovariectomy induces a marked increase in mean arterial pressure (MAP) that is abolished by renin angiotensin system (RAS) blockade, suggesting RAS involvement in the etiology of hypertension induced by ovariectomy in adult female growth-restricted offspring. Blockade of the RAS also abolishes hypertension in adult male growth-restricted offspring. Moreover, sensitivity to acute ANG II is enhanced in male growth-restricted offspring. Thus, we hypothesized that an enhanced sensitivity to acute ANG II may contribute to hypertension induced by ovariectomy in female growth-restricted offspring. Female offspring were subjected to ovariectomy (OVX) or sham ovariectomy (intact) at 10 wk of age. Cardio-renal hemodynamic parameters were determined before and after an acute infusion of ANG II (100 ng·kg(-1)·min(-1) for 30 min) at 16 wk of age in female offspring pretreated with enalapril (40 mg·kg(-1)·day(-1) for 7 days). Acute ANG II induced a significant increase in MAP in intact growth-restricted offspring (155 ± 2 mmHg, P < 0.05) relative to intact control (145 ± 4 mmHg). Ovariectomy augmented the pressor response to ANG II in growth-restricted offspring (163 ± 2 mmHg, P < 0.05), with no effect in control (142 ± 2 mmHg). Acute pressor responses to phenylephrine did not differ in growth-restricted offspring relative to control, intact, or ovariectomized. Furthermore, renal hemodynamic responses to acute ANG II were significantly enhanced only in ovariectomized female growth-restricted offspring. Thus, these data suggest that enhanced responsiveness to acute ANG II is programmed by intrauterine growth restriction and that sensitivity to acute ANG II is modulated by ovarian hormones in female growth-restricted offspring.