Chronic mistimed feeding results in renal fibrosis and disrupted circadian blood pressure rhythms.

Circadian disruption is a disturbance in biological timing, which can occur within or between different organizational levels, ranging from molecular rhythms within specific cells to the misalignment of behavioral and environmental cycles. Previous work from our group showed that less than 1 wk of food restriction to the light (inactive) period is sufficient to invert diurnal blood pressure rhythms in mice. However, kidney excretory rhythms and functions remained aligned with the light-dark cycle. Shift workers have an increased risk of cardiovascular disease that may different between sexes and often have irregular mealtimes, making the possibility of mistimed feeding as a potential contributor to the development of kidney disease. Thus, we hypothesized that chronic mistimed food intake would result in adverse cardiorenal effects, with sex differences in severity. Here, we show that chronic circadian disruption via mistimed feeding results in renal fibrosis and aortic stiffness in a sex-dependent manner. Our results indicate the importance of meal timing for the maintenance of blood pressure rhythms and kidney function, particularly in males. Our results also demonstrate that females are better able to acclimate to circadian-related behavioral change. NEW & NOTEWORTHY Circadian disruption through mistimed feeding resulted in nondipping blood pressure, renal fibrosis, and arterial stiffness that were less severe in females versus males. Mice fed exclusively during the daytime maintain their circadian rhythms of locomotor activity regardless of their loss of blood pressure rhythms. Although these mice ate less food, they maintained body weight, suggesting inefficiencies in overall metabolism. These findings demonstrate the importance of maintaining optimal food intake patterns to prevent cardiorenal pathophysiology.

Racial and ethnic differences in diagnosis age and blood biomarkers in a pediatric inflammatory bowel disease cohort.

OBJECTIVE: Prompt diagnosis of pediatric-onset inflammatory bowel disease (IBD) is crucial for preventing a complicated disease course; however, it is not well understood how social determinants of health might affect pediatric IBD diagnosis. This study examined differences in diagnosis age, biomarkers of disease severity, and anthropometrics with sociodemographic factors in a pediatric IBD cohort. METHODS: Pediatric IBD patients (n = 114) and their parents/caregivers were enrolled from the Children's of Alabama Pediatric IBD Clinic in Birmingham, Alabama. Primary analyses examined associations of child race and ethnicity, parental income, parental education, single-parent household status, insurance type, and distance to a tertiary pediatric gastroenterology referral center with diagnosis age. Secondary analyses examined differences in biomarker levels, height, and body mass index at the time of diagnosis. RESULTS: Racial and ethnic minority children were diagnosed at an older age compared to Non-Hispanic White children (14.4 ± 0.40 vs. 11.7 ± 0.38 years; p < 0.001), and this trend was robust to adjustment with other sociodemographic variables. Parental attainment of a college education attenuated the link between minority race and ethnicity and the likelihood of older age at diagnosis, while other sociodemographic variables had no moderating effect. Racial and ethnic minority children were 5.7 times more likely to have clinically elevated erythrocyte sedimentation rate at diagnosis compared to Non-Hispanic White children (p = .024). CONCLUSIONS: These results suggest that child race and ethnicity may exert a primary effect on the age at diagnosis with pediatric-onset IBD. This study highlights the need for further research on racial and ethnic disparities to promote health equity in pediatric-onset IBD.

Early Life Stress, Coping, and Cardiovascular Reactivity to Acute Social Stress.

OBJECTIVE: Early life stress (ELS) occurring during childhood and adolescence is an established risk factor for later cardiovascular disease and dysregulated reactivity to acute social stress. This study examined whether ELS associations with baseline cardiovascular functioning, cardiovascular stress reactivity and recovery, and emotional stress reactivity vary across levels of emotion-oriented, task-oriented, and avoidant coping styles. METHODS: The sample included 1027 adolescents and young adults (mean age = 19.29 years; 50% female; 64% Black, 34% non-Hispanic White) who reported on their ELS exposure and coping styles. Participants completed a standardized acute social stress test (the Trier Social Stress Test [TSST]), with heart rate (HR) and blood pressure (BP) measured before, during, and after the TSST. Self-reports of negative emotions during the TSST indexed emotional stress reactivity. RESULTS: Multiple regression models adjusting for demographic factors and body mass index showed that ELS was associated with lower HR stress reactivity, avoidant coping was related to lower systolic BP and diastolic BP during stress and lower systolic BP during recovery, and higher emotion-oriented coping and lower task-oriented coping predicted greater emotional stress reactivity. A consistent pattern emerged where emotion-oriented coping amplified the associations between ELS and maladaptive stress responses (blunted cardiovascular stress reactivity and recovery; enhanced emotional stress reactivity), whereas lower levels of emotion-oriented coping were associated with resilient profiles among those who experienced ELS (lower resting HR, lower emotional stress reactivity, average HR and BP stress reactivity and recovery). However, low levels of emotion-oriented coping also conferred a risk of higher BP during recovery for those with high levels of ELS. CONCLUSIONS: These results suggest that low to moderate levels of emotion-oriented coping promote optimal cardiovascular and emotional reactivity to acute stress among individuals exposed to ELS.

Adverse childhood experiences are associated with vascular changes in adolescents that are risk factors for future cardiovascular disease.

BACKGROUND: Adverse childhood experiences (ACEs), such as abuse, neglect, and household dysfunction, are associated with a higher risk of cardiovascular disease (CVD) and indicators of future CVD risk in adulthood, such as greater vascular stiffness. The impact of ACEs in adolescence is unclear, and understanding how ACEs relate to blood pressure (BP) and vascular function during early life is key for the development of prevention strategies to reduce CVD risk. We hypothesized that exposure to ACEs would be associated with changes in central hemodynamics such as increased vascular stiffness and higher BP during adolescence. METHODS: This pilot study enrolled 86 adolescents recruited from the Children's of Alabama. A validated ACE questionnaire was employed, and ACEs were modeled both as a continuous variable and a categorical variable (ACE ≥ 1 vs. ACE = 0). The primary outcomes used are considered to be indicators of future cardio-renal disease risk: aortic augmentation index normalized to 75 bpm (Alx75, a surrogate for vascular stiffness), carotid-femoral PWV (m/s), and ambulatory BP patterns. RESULTS: Adolescents with ACE ≥ 1 had significantly higher Alx75 (ACE: 5.2% ± 2.2 compared to no ACE: - 1.4% ± 3.0; p = 0.043). PWV only reflected this trend when adjustments were made for the body mass index. Adolescents with ACEs showed no differences in ambulatory BP patterns during the 24-h, wake, or sleep periods compared to adolescents with no ACEs. CONCLUSIONS: ACEs were associated with higher AIx75 in adolescence, which is a risk factor for future CVD. Adolescence could present an opportunity for early detections/interventions to mitigate adverse cardiovascular outcomes in adulthood. A higher resolution version of the Graphical abstract is available as Supplementary information.

High salt intake induces collecting duct HDAC1-dependent NO signaling.

We reported that high salt (HS) intake stimulates renal collecting duct (CD) endothelin (ET) type B receptor (ETBR)/nitric oxide (NO) synthase 1ß (NOS1ß)-dependent NO production inhibiting the epithelial sodium channel (ENaC) promoting natriuresis. However, the mechanism underlying the HS-induced increase of NO production is unclear. Histone deacetylase 1 (HDAC1) responds to increased fluid flow, as can occur in the CD during HS intake. The renal inner medulla (IM), in particular the IMCD, has the highest NOS1 activity within the kidney. Hence, we hypothesized that HS intake provokes HDAC1 activation of NO production in the IM. HS intake for 1 wk significantly increased HDAC1 abundance in the IM. Ex vivo treatment of dissociated IM from HS-fed mice with a selective HDAC1 inhibitor (MS-275) decreased NO production with no change in ET-1 peptide or mRNA levels. We further investigated the role of the ET-1/ETBR/NOS1ß signaling pathway with chronic ETBR blockade (A-192621). Although NO was decreased and ET-1 levels were elevated in the dissociated IM from HS-fed mice treated with A-192621, ex vivo MS-275 did not further change NO or ET-1 levels suggesting that HDAC1-mediated NO production is regulated at the level or downstream of ETBR activation. In split-open CDs from HS-fed mice, patch clamp analysis revealed significantly higher ENaC activity after MS-275 pretreatment, which was abrogated by an exogenous NO donor. Moreover, flow-induced increases in mIMCD-3 cell NO production were blunted by HDAC1 or calcium inhibition. Taken together, these findings indicate that HS intake induces HDAC1-dependent activation of the ETBR/NO pathway contributing to the natriuretic response.

Early life stress in mice alters gut microbiota independent of maternal microbiota inheritance.

Exposure to early life stress (ELS) is associated with a greater risk of chronic disease development including depression and cardiovascular disease. Altered gut microbiota has been linked to both depression and cardiovascular disease in mice and humans. Rodent models of early life neglect are used to characterize the mechanistic links between early life stress (ELS) and the risk of disease later in life. However, little is understood about ELS exposure and the gut microbiota in the young mice and the influence of the maternal inheritance of the gut microbiota. We used a mouse model of ELS, maternal separation with early weaning (MSEW), and normally reared mice to determine whether the neonate microbiota is altered, and if so, are the differences attributable to changes in dam microbiota that are then transmitted to their offspring. Individual amplicon sequence variants (ASVs) displayed differential abundance in the microbiota of MSEW compared with normally reared pups at postnatal day (PD) 28. Additionally, ELS exposure reduced the alpha diversity and altered microbial community composition at PD28. The composition, levels of alpha diversity, and abundance of individual ASVs in the microbiota of dams were similar from MSEW or normally reared cohorts. Thus, the observed shifts in the abundance of individual bacterial ASVs in the neonates and young pups are likely driven by endogenous effects of MSEW in the offspring host and are not due to inherited differences from the dam. This knowledge suggests that exposure to ELS has a direct effect on microbial factors on the risk of chronic disease development.

Hydroxyurea improves nitric oxide bioavailability in humanized sickle cell mice.

Despite advancements in disease management, sickle cell nephropathy, a major contributor to mortality and morbidity in patients, has limited therapeutic options. Previous studies indicate hydroxyurea, a commonly prescribed therapy for sickle cell disease (SCD), can reduce renal injury in SCD but the mechanisms are uncertain. Because SCD is associated with reduced nitric oxide (NO) bioavailability, we hypothesized that hydroxyurea treatment would improve NO bioavailability in the humanized sickle cell mouse. Humanized male 12-wk-old sickle (HbSS) and genetic control (HbAA) mice were treated with hydroxyurea or regular tap water for 2 wk before renal and systemic NO bioavailability as well as renal injury were assessed. Untreated HbSS mice exhibited increased proteinuria, elevated plasma endothelin-1 (ET-1), and reduced urine concentrating ability compared with HbAA mice. Hydroxyurea reduced proteinuria and plasma ET-1 levels in HbSS mice. Untreated HbSS mice had reduced plasma nitrite and elevated plasma arginase concentrations compared with HbAA mice. Hydroxyurea treatment augmented plasma nitrite and attenuated plasma arginase in HbSS mice. Renal vessels isolated from HbSS mice also had elevated nitric oxide synthase 3 (NOS3) and arginase 2 expression compared with untreated HbAA mice. Hydroxyurea treatment did not alter renal vascular NOS3, however, renal vascular arginase 2 expression was significantly reduced. These data support the hypothesis that hydroxyurea treatment augments renal and systemic NO bioavailability by reducing arginase activity as a potential mechanism for the improvement on renal injury seen in SCD mice.

Liver circadian clock disruption alters perivascular adipose tissue gene expression and aortic function in mice.

The liver plays a central role that influences cardiovascular disease outcomes through regulation of glucose and lipid metabolism. It is recognized that the local liver molecular clock regulates some liver-derived metabolites. However, it is unknown whether the liver clock may impact cardiovascular function. Perivascular adipose tissue (PVAT) is a specialized type of adipose tissue surrounding blood vessels. Importantly, cross talk between the endothelium and PVAT via vasoactive factors is critical for vascular function. Therefore, we designed studies to test the hypothesis that cardiovascular function, including PVAT function, is impaired in mice with liver-specific circadian clock disruption. Bmal1 is a core circadian clock gene, thus studies were undertaken in male hepatocyte-specific Bmal1 knockout (HBK) mice and littermate controls (i.e., flox mice). HBK mice showed significantly elevated plasma levels of ß-hydroxybutyrate, nonesterified fatty acids/free fatty acids, triglycerides, and insulin-like growth factor 1 compared with flox mice. Thoracic aorta PVAT in HBK mice had increased mRNA expression of several key regulatory and metabolic genes, Ppargc1a, Pparg, Adipoq, Lpl, and Ucp1, suggesting altered PVAT energy metabolism and thermogenesis. Sensitivity to acetylcholine-induced vasorelaxation was significantly decreased in the aortae of HBK mice with PVAT attached compared with aortae of HBK mice with PVAT removed, however, aortic vasorelaxation in flox mice showed no differences with or without attached PVAT. HBK mice had a significantly lower systolic blood pressure during the inactive period of the day. These new findings establish a novel role of the liver circadian clock in regulating PVAT metabolic gene expression and PVAT-mediated aortic vascular function.

Activation of G protein-coupled estrogen receptor 1 ameliorates proximal tubular injury and proteinuria in Dahl salt-sensitive female rats.

Recent evidence indicates a crucial role for G protein-coupled estrogen receptor 1 (GPER1) in the maintenance of cardiovascular and kidney health in females. The current study tested whether GPER1 activation ameliorates hypertension and kidney damage in female Dahl salt-sensitive (SS) rats fed a high-salt (HS) diet. Adult female rats were implanted with telemetry transmitters for monitoring blood pressure and osmotic minipumps releasing G1 (selective GPER1 agonist, 400 µg/kg/day ip) or vehicle. Two weeks after pump implantation, rats were shifted from a normal-salt (NS) diet (0.4% NaCl) to a matched HS diet (4.0% NaCl) for 2 wk. Twenty-four hour urine samples were collected during both diet periods and urinary markers of kidney injury were assessed. Histological assessment of kidney injury was conducted after the 2-wk HS diet period. Compared with values during the NS diet, 24-h mean arterial pressure markedly increased in response to HS, reaching similar values in vehicle-treated and G1-treated rats. HS also significantly increased urinary excretion of protein, albumin, nephrin (podocyte damage marker), and KIM-1 (proximal tubule injury marker) in vehicle-treated rats. Importantly, G1 treatment prevented the HS-induced proteinuria, albuminuria, and increase in KIM-1 excretion but not nephrinuria. Histological analysis revealed that HS-induced glomerular damage did not differ between groups. However, G1 treatment preserved proximal tubule brush-border integrity in HS-fed rats. Collectively, our data suggest that GPER1 activation protects against HS-induced proteinuria and albuminuria in female Dahl SS rats by preserving proximal tubule brush-border integrity in a blood pressure-independent manner.

Loss of circadian gene Bmal1 in the collecting duct lowers blood pressure in male, but not female, mice.

Kidney function follows a 24-h rhythm subject to regulation by circadian genes including the transcription factor Bmal1. A high-salt diet induces a phase shift in Bmal1 expression in the renal inner medulla that is dependent on endothelin type B (ETB) receptors. Furthermore, ETB receptor-mediated natriuresis is sex dependent. Therefore, experiments tested the hypothesis that collecting duct Bmal1 regulates blood pressure in a sex-dependent manner. We generated a mouse model that lacks Bmal1 expression in the collecting duct, where ETB receptor abundance is highest. Male, but not female, collecting duct Bmal1 knockout (CDBmal1KO) mice had significantly lower 24-h mean arterial pressure (MAP) than flox controls (105 ± 2 vs. 112 ± 3 mmHg for male mice and 106 ± 1 vs. 108 ± 1 mmHg for female mice, by telemetry). After 6 days on a high-salt (4% NaCl) diet, MAP remained significantly lower in male CDBmal1KO mice than in male flox control mice (107 ± 2 vs. 113 ± 1 mmHg), with no significant differences between genotypes in female mice (108 ± 2 vs. 109 ± 1 mmHg). ETB receptor blockade for another 6 days increased MAP similarly in both male and female CDBmal1KO and flox control mice. However, MAP remained lower in male CDBmal1KO mice than in male flox control mice (124 ± 2 vs. 130 ± 2 mmHg). No significant differences were observed between female CDBmal1KO and flox mice during ETB blockade (130 ± 2 vs. 127 ± 2 mmHg). There were no significant genotype differences in amplitude or phase of MAP in either sex. These data suggest that collecting duct Bmal1 has no role in circadian MAP but plays an important role in overall blood pressure in male, but not female, mice.

Sirt1 during childhood is associated with microvascular function later in life.

Microvascular dysfunction often precedes other age-related macrovascular conditions and predicts future cardiovascular risk. Sirtuin 1 (Sirt1) has recently emerged as a protein that protects the vasculature and reduces the risk of cardiovascular diseases. We tested the hypothesis that lower Sirt1 during childhood is associated with a reduced microvascular function during adulthood. Thirty-four adults (34 ± 3 yr) from the Augusta Heart Study returned to participate in the present clinical observational study. Sirt1 was assessed in samples collected during both adulthood and participants' childhood (16 ± 3 yr), and data were divided based on childhood Sirt1 concentrations: <3 ng/dL (LowCS; n = 16) and ≥3 ng/dL (HighCS; n = 18). MVF was evaluated in all of the adults using laser-Doppler flowmetry coupled with three vascular reactivity tests: 1) local thermal hyperemia (LTH), 2) post-occlusive reactive hyperemia (PORH), and 3) iontophoresis of acetylcholine (ACh). The hyperemic response to LTH was significantly (P ≤ 0.044) lower in the LowCS than in the HighCS group. Similarly, the LowCS also exhibited an ameliorated (P ≤ 0.045) response to the PORH test and lower (P ≤ 0.008) vasodilation in response to iontophoresis of ACh when compared with the HighCS. Positive relationships were identified between childhood Sirt1 and all MVF reactivity tests (r≥0.367, P ≤ 0.004). Novel observations suggest that lower Sirt1 during childhood is associated with premature microvascular dysfunction in adulthood. These findings provide evidence that Sirt1 may play a critical role in microvascular function and have therapeutic potential for the prevention of age-associated vascular dysfunction in humans.NEW & NOTEWORTHY With a longitudinal cohort, novel observations from the present study demonstrate that individuals who had lower Sirt1 early in life exhibit premature microvascular dysfunction during adulthood and may be at higher risk to develop CVD. These results provide experimental evidence that Sirt1 may play an important role in microvascular function with age and represent a potential therapeutic target to prevent premature vascular dysfunction.

Endothelin.

The endothelins comprise three structurally similar 21-amino acid peptides. Endothelin-1 and -2 activate two G-protein coupled receptors, ETA and ETB, with equal affinity, whereas endothelin-3 has a lower affinity for the ETA subtype. Genes encoding the peptides are present only among vertebrates. The ligand-receptor signaling pathway is a vertebrate innovation and may reflect the evolution of endothelin-1 as the most potent vasoconstrictor in the human cardiovascular system with remarkably long lasting action. Highly selective peptide ETA and ETB antagonists and ETB agonists together with radiolabeled analogs have accurately delineated endothelin pharmacology in humans and animal models, although surprisingly no ETA agonist has been discovered. ET antagonists (bosentan, ambrisentan) have revolutionized the treatment of pulmonary arterial hypertension, with the next generation of antagonists exhibiting improved efficacy (macitentan). Clinical trials continue to explore new applications, particularly in renal failure and for reducing proteinuria in diabetic nephropathy. Translational studies suggest a potential benefit of ETB agonists in chemotherapy and neuroprotection. However, demonstrating clinical efficacy of combined inhibitors of the endothelin converting enzyme and neutral endopeptidase has proved elusive. Over 28 genetic modifications have been made to the ET system in mice through global or cell-specific knockouts, knock ins, or alterations in gene expression of endothelin ligands or their target receptors. These studies have identified key roles for the endothelin isoforms and new therapeutic targets in development, fluid-electrolyte homeostasis, and cardiovascular and neuronal function. For the future, novel pharmacological strategies are emerging via small molecule epigenetic modulators, biologicals such as ETB monoclonal antibodies and the potential of signaling pathway biased agonists and antagonists.

Early life stress induces immune priming in kidneys of adult male rats.

Early life stress (ELS) in humans is associated with elevated proinflammatory markers. We hypothesized that ELS induces activation of the immune response in a rat model of ELS, maternal separation (MatSep), in adulthood. MatSep involves separating pups from the dam from postnatal day 2 to postnatal day 14 for 3 h/day. Control rats are nonseparated littermates. We determined circulating and renal immune cell numbers, renal immune cell activation markers, renal cytokine levels, and the renal inflammatory gene expression response to low-dose lipopolysaccharide (LPS) in male MatSep and control rats. We observed that MatSep did not change the percentage of gated events for circulating CD3+, CD4+, CD8+, and CD4+/Foxp3+ cells or absolute numbers of mononuclear and T cells in the circulation and kidneys; however, MatSep led to an increase in activation of renal neutrophils as well as CD44+ cells. Renal toll-like receptor 4 (TLR4) and interleukin 1 beta (IL-1ß) was significantly increased in MatSep rats, specifically in the outer and inner medulla and distal nephron, respectively. Evaluation of renal inflammatory genes showed that in response to a low-dose LPS challenge (2 mg/kg iv) a total of 20 genes were significantly altered in kidneys from MatSep rats (17 genes were upregulated and 3 were downregulated), as opposed to no significant differences in gene expression in control vs. control + LPS groups. Taken together, these findings indicate that MatSep induces priming of the immune response in the kidney.

High dietary sodium causes dyssynchrony of the renal molecular clock in rats.

Speed JS, Hyndman KA, Roth K, Heimlich JB, Kasztan M, Fox BM, Johnston JG, Becker BK, Jin C, Gamble KL, Young ME, Pollock JS, Pollock DM. High dietary sodium causes dyssynchrony of the renal molecular clock in rats. Am J Physiol Renal Physiol 314: F89-F98, 2018. First published September 27, 2017; doi:10.1152/ajprenal.00028.2017.-Dyssynchrony of circadian rhythms is associated with various disorders, including cardiovascular and metabolic diseases. The cell autonomous molecular clock maintains circadian control; however, environmental factors that may cause circadian dyssynchrony either within or between organ systems are poorly understood. Our laboratory recently reported that the endothelin (ET-1) B (ETB) receptor functions to facilitate Na+ excretion in a time of day-dependent manner. Therefore, the present study was designed to determine whether high salt (HS) intake leads to circadian dyssynchrony within the kidney and whether the renal endothelin system contributes to control of the renal molecular clock. We observed that HS feeding led to region-specific alterations in circadian clock components within the kidney. For instance, HS caused a significant 5.5-h phase delay in the peak expression of Bmal1 and suppressed Cry1 and Per2 expression in the renal inner medulla, but not the renal cortex, of control rats. The phase delay in Bmal1 expression appears to be mediated by ET-1 because this phenomenon was not observed in the ETB-deficient rat. In cultured inner medullary collecting duct cells, ET-1 suppressed Bmal1 mRNA expression. Furthermore, Bmal1 knockdown in these cells reduced epithelial Na+ channel expression. These data reveal that HS feeding leads to intrarenal circadian dyssynchrony mediated, in part, through activation of ETB receptors within the renal inner medulla.

Maternal separation enhances anticontractile perivascular adipose tissue function in male rats on a high-fat diet.

Clinical studies have shown that obesity negatively impacts large arteries' function. We reported that rats exposed to maternal separation (MatSep), a model of early life stress, display enhanced angiotensin II (ANG II)-induced vasoconstriction in aortic rings cleaned of perivascular adipose tissue (PVAT) under normal diet (ND) conditions. We hypothesized that exposure to MatSep promotes a greater loss of PVAT-mediated protective effects on vascular function and loss of blood pressure (BP) rhythm in rats fed a high-fat diet (HFD) when compared with controls. MatSep was performed in male Wistar-Kyoto rats from days 2 to 14 of life. Normally reared littermates served as controls. On ND, aortic rings from MatSep rats with PVAT removed showed increased ANG II-mediated vasoconstriction versus controls; however, rings from MatSep rats with intact PVAT displayed blunted constriction. This effect was exacerbated by an HFD in both groups; however, the anticontractile effect of PVAT was greater in MatSep rats. Acetylcholine-induced relaxation was similar in MatSep and control rats fed an ND, regardless of the presence of PVAT. HFD impaired aortic relaxation in rings without PVAT from MatSep rats, whereas the presence of PVAT improved relaxation in both groups. On an HFD, immunolocalization of vascular smooth muscle-derived ANG-(1-7) and PVAT-derived adiponectin abundances were increased in MatSep. In rats fed an HFD, 24-h BP and BP rhythms were similar between groups. In summary, MatSep enhanced the ability of PVAT to blunt the heightened ANG II-induced vasoconstriction and endothelial dysfunction in rats fed an HFD. This protective effect may be mediated via the upregulation of vasoprotective factors within the adipovascular axis.

Influence of the selective COX-2 inhibitor celecoxib on sex differences in blood pressure and albuminuria in spontaneously hypertensive rats.

We previously reported that female spontaneously hypertensive rats (SHR) have greater cyclooxygenase-2 (COX-2) expression in the renal medulla and enhanced urinary excretion of prostaglandin (PG) E2 (PGE2) metabolites compared to male SHR. Based on the role of COX-2-derived prostanoids in the regulation of cardiovascular health, the aim of the current study was to test the hypothesis that blood pressure (BP) in female SHR is more sensitive to COX-2 inhibition than in males. Seven week old male and female SHR were implanted with telemetry transmitters for continuous BP recording. After one week of baseline BP recording, male and female SHR were randomized to receive the selective COX-2 inhibitor celecoxib (10 mg/kg/day) or vehicle for six weeks (from 9 to 14 weeks of age). Female SHR had lower BP and albuminuria compared to male SHR as well as enhanced urinary excretion of PGE metabolite (PGEM), 6-keto PGF1α and thromboxane B2, indicators of PGE2, PGI2 and TXA2, respectively. Treatment with celecoxib did not significantly alter BP or albuminuria in either female or male SHR. Celecoxib did not change PGs metabolites excretion in male SHR; however, excretion levels of PGEM and 6-keto PGF1α were reduced in female SHR. COX-2 derived PG can also induce oxidative stress. Markers of oxidative stress (thiobarbituric acid reactive substances (TBARs) and H2O2 excretion) were lesser in female SHR versus male SHR. Celecoxib treatment did not significantly change markers of oxidative stress in female SHR, however, urinary TBARs excretion was significantly reduced in male SHR after 6 weeks of treatment with celecoxib. Therefore, although celecoxib treatment appears to have distinct effects on prostanoids levels in female SHR vs. males, it is unlikely that COX-2 contributes to established sex differences in BP in SHR.

Long-Term Endothelin-A Receptor Antagonism Provides Robust Renal Protection in Humanized Sickle Cell Disease Mice.

Sickle cell disease (SCD)-associated nephropathy is a major source of morbidity and mortality in patients because of the lack of efficacious treatments targeting renal manifestations of the disease. Here, we describe a long-term treatment strategy with the selective endothelin-A receptor (ETA) antagonist, ambrisentan, designed to interfere with the development of nephropathy in a humanized mouse model of SCD. Ambrisentan preserved GFR at the level of nondisease controls and prevented the development of proteinuria, albuminuria, and nephrinuria. Microscopy studies demonstrated prevention of podocyte loss and structural alterations, the absence of vascular congestion, and attenuation of glomerulosclerosis in treated mice. Studies in isolated glomeruli showed that treatment reduced inflammation and oxidative stress. At the level of renal tubules, ambrisentan treatment prevented the increased excretion of urinary tubular injury biomarkers. Additionally, the treatment strategy prevented tubular brush border loss, diminished tubular iron deposition, blocked the development of interstitial fibrosis, and prevented immune cell infiltration. Furthermore, the prevention of albuminuria in treated mice was associated with preservation of cortical megalin expression. In a separate series of identical experiments, combined ETA and ETB receptor antagonism provided only some of the protection observed with ambrisentan, highlighting the importance of exclusively targeting the ETA receptor in SCD. Our results demonstrate that ambrisentan treatment provides robust protection from diverse renal pathologies in SCD mice, and suggest that long-term ETA receptor antagonism may provide a strategy for the prevention of renal complications of SCD.

Renal denervation attenuates hypertension but not salt sensitivity in ETB receptor-deficient rats.

Hypertension is a prevalent pathology that increases risk for numerous cardiovascular diseases. Because the etiology of hypertension varies across patients, specific and effective therapeutic approaches are needed. The role of renal sympathetic nerves is established in numerous forms of hypertension, but their contribution to salt sensitivity and interaction with factors such as endothelin-1 are poorly understood. Rats deficient of functional ETB receptors (ETB-def) on all tissues except sympathetic nerves are hypertensive and exhibit salt-sensitive increases in blood pressure. We hypothesized that renal sympathetic nerves contribute to hypertension and salt sensitivity in ETB-def rats. The hypothesis was tested through bilateral renal sympathetic nerve denervation and measuring blood pressure during normal salt (0.49% NaCl) and high-salt (4.0% NaCl) diets. Denervation reduced mean arterial pressure in ETB-def rats compared with sham-operated controls by 12 ± 3 (SE) mmHg; however, denervation did not affect the increase in blood pressure after 2 wk of high-salt diet (+19 ± 3 vs. +16 ± 3 mmHg relative to normal salt diet; denervated vs. sham, respectively). Denervation reduced cardiac sympathetic-to-parasympathetic tone [low frequency-high frequency (LF/HF)] during normal salt diet and vasomotor LF/HF tone during high-salt diet in ETB-def rats. We conclude that the renal sympathetic nerves contribute to the hypertension but not to salt sensitivity of ETB-def rats.

Adverse childhood experiences and blood pressure trajectories from childhood to young adulthood: the Georgia stress and Heart study.

BACKGROUND: The purposes of this study were to assess the long-term effect of adverse childhood experiences (ACEs) on blood pressure (BP) trajectories from childhood to young adulthood and to examine whether this relation is explained by childhood socioeconomic status (SES) or risk behaviors that are associated with ACEs. METHODS AND RESULTS: Systolic and diastolic BPs were measured up to 16 times (13 times on average) over a 23-year period in 213 African Americans and 181 European Americans 5 to 38 years of age. Retrospective data on traumatic experiences before 18 years of age were collected, including abuse, neglect, and household dysfunction. Individual growth curve modeling within a multilevel framework was used to examine the relation between exposure to ACEs and BP development. No main effect of ACEs on average BP levels was found. However, a significant interaction of ACE score with age(3) was observed (systolic BP, P=0.033; diastolic BP, P=0.017). Subjects who experienced multiple traumatic events during childhood showed a faster rise in BP levels after 30 years of age than those without ACEs. As expected, a graded association of ACEs with childhood socioeconomic status and negative health behaviors was observed (P<0.001). The ACE-systolic BP relation was not explained by these factors, whereas the ACE-diastolic BP relation was partially mediated by illicit drug use. CONCLUSION: In this novel longitudinal study, we observed that participants who were exposed to multiple ACEs displayed a greater increase in BP levels in young adulthood compared with their counterparts without ACEs.