Blood Pressure Homeostasis Research Articles

Beyond the gastrointestinal tract: oral and sex-specific skin microbiota are associated with hypertension in rats with genetic disparities.

Current knowledge of the link between microbiota and hypertension is limited to the gut. Besides the gut, oral cavity and skin are other locations where sodium chloride (NaCl) is in direct contact with microbiota. Although oral nitrate-reducing bacteria generate nitric oxide, which leads to vasodilation and lowering of blood pressure (BP), the skin excretes sodium via sweat glands and is an important site for sodium and BP homeostasis. However, knowledge on the contributions of oral and skin microbiota to BP regulation, is limited. Therefore, the current study was conducted to compare the tripartite relationship between site, sex, and genetic effects on the composition of oral, skin, and gut microbiota impacting hypertension. Microbiota were profiled from the oral cavity, skin, and feces of both male and female hypertensive Dahl salt-sensitive (S) and congenic rats with genomic substitutions on rat chromosomes (RNO) 1, 5, 9, and 10, demonstrating disparate BP effects. Sex-specific differences in β-diversity were observed only in skin microbiota. The most abundant taxa of the oral and skin microbiota were Actinobacteria and Cyanobacteria, respectively. Oral Actinobacteria were inversely associated with BP. Although the abundance of oral Actinobacteria was upregulated by the BP locus on RNO10 in both sexes, depletion of skin Cyanobacteria decreased the protection from hypertension in the RNO5 female, but not male, congenic strain. In conclusion, to our knowledge this is the first study to identify specific microbiota in sites other than gut as contributors to BP regulation. Notably, both oral Actinobacteria and skin Cyanobacteria were beneficial for lowering BP.

Phospholipase D2 Loss Impairs Low Salt‐Induced Increases in Steroidogenic Gene Expression with No Effect on Serum Aldosterone Levels

Primary aldosteronism (PA), in which plasma aldosterone levels are normal or elevated relative to suppressed plasma renin levels, is the most frequent cause of secondary hypertension. PA accounts for 5‐10% of hypertension cases and up to 20% in those with resistant hypertension. Aldosterone is a mineralocorticoid hormone responsible for maintaining fluid volume, electrolyte balance, and blood pressure homeostasis; it is tightly regulated by the renin‐angiotensin‐aldosterone system. Our laboratory has previously shown that phospholipase D2 (PLD2) mediates angiotensin II‐induced aldosterone synthesis and secretion in vitro. Therefore, we hypothesized that PLD2 loss would result in decreased aldosterone production in vivo. To test this hypothesis, 11‐week‐old male and female wild‐type and PLD2‐/‐ mice were fed a high salt (1% NaCl) or a low salt (0.02% NaCl; to raise endogenous serum angiotensin II levels) diet for 24 hours. Adrenal steroidogenic gene expression and serum aldosterone, corticosterone, and electrolytes were measured by qRT‐PCR, radioimmunoassay, ELISA, and atomic absorption spectrometry, respectively. The PLD2‐/‐ male mice exhibited increased StAR, Dab2, and CYP11B1 expression; further, PLD2 loss impaired low salt‐induced increases in StAR, Dab2, and CYP11B1 expression; however, PLD2 loss had no effect on CYP11B2 expression or serum aldosterone, Na+, K+, and corticosterone levels in these male mice. These data suggest that increased steroidogenic enzyme expression may compensate for PLD2 loss in order to maintain aldosterone secretion in the males. On the other hand, the PLD2‐/‐ female mice exhibited decreased StAR and CYP11B1 expression and serum Na+ levels as well as impaired low salt‐induced increases in StAR, CYP11B2, Dab2, and CYP11B1 expression. PLD2 loss had no effect on serum aldosterone, K+, or corticosterone levels in these female mice. It is possible that other compensatory mechanisms (not involving steroidogenic enzymes) might be involved in maintaining aldosterone secretion in the females. Together, our findings suggest a likely importance of PLD2 in mediating aldosterone production and steroidogenic enzyme gene expression, with differential effects in male and female mice.

Changes in systolic blood pressure, postprandial glucose, and gut microbial composition following mango consumption in individuals with overweight and obesity.

This study aimed to explore the impact of daily mango consumption (Mangifera indica) on cardiometabolic health and gut microbiota in individuals with overweight and obesity. Changes in cardiometabolic variables, gut microbiota diversity and composition, physical activity habits, and dietary intakes were assessed in 8 males and 19 females with overweight and obesity who consumed 280g/day of mango pulp for 8weeks. There were no significant changes in body weight, waist circumference, or plasma lipid levels. However, after consuming mangos for 8weeks, participants showed a 3.5% reduction in systolic blood pressure (-4 ± 6mmHg, p= 0.011) as well as a 10.5% reduction in 2-hour plasma glucose concentration after a 75-g oral glucose tolerance test (-0.58 ± 1.03 mmol/L, p= 0.008). These beneficial cardiometabolic outcomes were accompanied with enhanced gut microbiota diversity and with changes in the abundance of specific gut bacterial species. Mango consumption may have beneficial effects on both blood pressure and glucose homeostasis in individuals with overweight and obesity. Further studies are warranted to determine the impact of long-term and regular mango intake on cardiometabolic risk factors of individuals with overweight and obesity, and the potential mechanisms linking gut microbial changes to those health benefits. This study was registered with clinicaltrials.gov as NCT03825276. Novelty: A 3.5% reduction in systolic blood pressure is noted after consuming mangos for 8 weeks. A 10.5% reduction in 2-hour plasma glucose concentration of an oral glucose tolerance test is observed after consuming mangos for 8 weeks. Mango consumption for 8 weeks may enhance gut microbial diversity and abundance of specific bacterial species.

Abstract #1183049: Hypertension (HTN) and Diabetes (DM) Improvement During Osilodrostat Therapy in Patients with Cushing’s Disease (CD): Analyses from the Phase III LINC 3 study

CD is a deleterious hypercortisolism disorder. Alleviating the burden of CD-associated comorbidities, including HTN and DM, is a key treatment goal. Osilodrostat, a potent oral 11β-hydroxylase inhibitor, normalized urinary free cortisol (UFC) and improved clinical signs and symptoms in CD patients (pts) in the Phase III LINC 3 study (NCT02180217). We describe blood pressure (BP) and glucose homeostasis changes in pts with baseline (BL) HTN and DM.

Glucose homeostasis is impaired in Guanylyl Cyclase/Natriuretic Peptide Receptor‐A Gene‐Knockout and Gene‐Duplication Mutant Mice

Atrial and brain natriuretic peptides (ANP and BNP) are produced in the heart, regulate blood pressure (BP) and fluid homeostasis through vasodilatory and diuretic actions. Both ANP and BNP act by binding to guanylyl cyclase/natriuretic peptide receptor‐A (GC‐A/NPR‐A). Systemic disruption of Npr1(encoding GC‐A/NPRA) leads to volume overload, high BP, and congestive heart failure. However, the underlying mechanisms are not yet precisely determined. The aim of this study was to investigate whether Npr1plays a critical role in regulating glucose homeostasis in Npr1 gene‐disrupted mice. The adult male and female (16‐18 wk) Npr1 gene‐knockout haplotype (Npr1+/‐, 1‐copy), wild‐type (Npr1+/+, 2‐copy), and gene‐duplicated (Npr1+ +/+ +, 4‐copy) mice were fasted for 16 h and given free access to water. The glucose administration was done both orally and intraperitoneally (IP: 2 g/kg body weight) in mice to determine oral glucose tolerance test (OGTT) and IP glucose tolerance test (IPGTT). The glucose levels in blood were determined by performing tail bleeds at 0, 15, 30, 60, 90, and 120 min using the AlphaTRAK blood glucose monitoring system (Zoetis Inc, Kalamazoo, MI). Systolic BP (SBP) was determined by non‐invasive computerized tail‐cuff method (Visitech 2000). The results showed that the blood glucose level was elevated to the maximum value at 15 min after glucose administration. Glucose levels were declined to near base line at 120 min in 2 copy mice (OGTT: 102 ± 3 mg/dL in male and 97 ± 4 mg/dL in female, IPGT: 101 ± 4 mg/dL in male and 96 ± 3 mg/dL in female). However, in 1‐copy mice, the blood glucose levels remained elevated even after 120 min (OGTT: 248 ± 5 mg/dL in male and 226 ± 3 mg/dL in female, IPGT: 254 ± 4 mg/dL in male and 229 ± 5 mg/dL in female) compared with 2‐copy mice. The blood glucose levels were also significantly lower at 120 min in 4‐copy mice (OGTT: 77 ± 4 mg/dL in male and 74 ± 3 mg/dL in female, IPGT: 75 ± 3 mg/dL in male and 71 ± 2 mg/dL in female) compared with 2‐copy mice. SBP was significantly greater in 1‐copy mice (137 + 4 mmHg in male and 126 + 3 mmHg in female) than 2‐copy mice (100 + 2 mmHg in male and 91 + 2 mmHg in female). SBP was significantly lower in 4‐copy mice (83 + 2 mmHg in male and 77 + 2 mmHg in female) than 2‐copy mice. OGTT showed a significantly lower level of maximal blood glucose compared with IPGTT. The findings of the present study suggest that Npr1 plays a critical role in the regulation of glucose homeostasis and the loss of Npr1 significantly increases the glucose levels in mutant animals.

Sexual Dimorphic Regulation of MicroRNAs Alters Sodium Transport in the Kidney Distal Nephron

BackgroundHypertension affects more than one billion people worldwide. A key regulator of blood pressure homeostasis is aldosterone, the final signaling hormone of the renin‐angiotensin‐aldosterone‐signaling (RAAS) system. Aldosterone increases sodium (Na+) transport in the kidney distal nephron to regulate blood volume. Premenopausal women are less likely to develop hypertension than age‐matched men, due to both lower aldosterone levels and estrogen signaling. We previously demonstrated that aldosterone alters the expression of microRNAs (miRs) in collecting duct epithelial cells to modulate the Na+ transport response to aldosterone. However, the sex‐specific regulation of miRs and role of estrogen to alter miR expression in the kidney distal nephron has not been explored. This study investigated the hypothesis that estrogen alters aldosterone signaling in the distal nephron by regulating the expression of miRs in collecting duct epithelia.MethodsPrimary cortical collecting duct (CCD) cells derived from male and female mice as well as the mCCD‐cl1 cell line were cultured on permeable filter supports to measure Na+ transport by short‐circuit current recordings in Ussing chambers. Cells were incubated with estrogen for time and dose responses to determine the impact on aldosterone stimulation and Na+ transport. RT‐qPCR quantified miR and mRNA expression and western blot analysis quantified protein expression after aldosterone and estrogen stimulation. In vivo regulation of miRs by aldosterone was confirmed using freshly isolated CCD cells from male and female mice placed on low Na+ diets.ResultsA sex‐specific upregulation of the miR‐17~92 cluster was observed in female mice placed on a low‐Na+ diet to stimulate aldosterone release. MiRs‐19a&b were also upregulated in mCCD cells stimulated with estrogen. Estrogen pretreatment blunted aldosterone stimulation, by targeting the serum and glucocorticoid induced kinase (SGK1) mRNA. Luciferase assays demonstrated that miRs‐19a&b bind to the 3’‐UTR of SGK1. Overexpression of miR‐19 in mCCD cells using miR mimics significantly inhibited aldosterone stimulation of Na+ transport. Conversely, aldosterone stimulation was greater in mCCD cells transfected with a miR‐19 inhibitor (antagomir).ConclusionThe miR‐17~92 cluster is regulated by aldosterone and estrogen. Mir‐19 targets SGK1 and may account for estrogen’s inhibition of aldosterone signaling. This miR cluster may be responsible, in part, for the observed sex‐specific differences in aldosterone signaling. Ongoing studies aim to determine if altering the expression of miR‐17~92 disrupts RAAS signaling in the kidney in vivo.

Angiotensin Ii‐induced Hypertension and Glomerular and Tubulointerstitial Injury in Mutant Mice With Kidney Proximal Tubule‐selective Deletion of Mitochondrial Nad+‐dependent Deacetylase Sirtuin 3: Focus on Sex Differences

Sirtuin 3 (SIRT3) is a major mitochondrial NAD‐dependent Deacetylase closely involved in energy production, cell metabolism, oxidative stress responses, and mitochondrial homeostasis during hypertension and kidney diseases. However, it remains unknown whether deletion of SIRT3 in the proximal tubules alters the hypertensive and kidney glomerular and tubulointerstitial fibrotic responses to angiotensin II (Ang II) in sex‐dependent manners. In the present study, adult male and female wild‐type (WT) and mutant mice with proximal tubule‐specific deletion of SIRT3, PT‐Sirt3‐/‐, were infused without (time controls) or with a slow pressor dose of Ang II via an osmotic minipump (0.5 mg/kg/day, i.p.), supplemented with a 2% NaCI diet or losartan, 20 mg/kg/day, for 2 weeks. Systolic (SBP), diastolic (DBP), and mean arterial blood (MAP) pressure were determined using the tail‐cuff method, whereas 24 hr. urinary sodium and potassium excretion were determined using a metabolic cage. Serum and urine creatinine were measured using colorimetric assays, whereas glomerular and tubulointerstitial injury was evaluated by Masson’s Trichrome staining. Basal SBP, DBP, and MAP were significantly lower in PT‐Sirt3‐/‐ mice than WT (WT‐SBP: 112 ± 2 vs. PT‐Sirt3‐/‐‐SBP: 93 ± 2 mmHg, P<0,01). The magnitude of Ang II‐induced hypertension was similar between WT and PT‐Sirt3‐/‐ mice with or without losartan treatment. After the establishment of hypertension, both WT and PT‐Sirt3‐/‐ animals significantly increased urine creatinine levels in both males and females (P<0.05). However, male PT‐Sirt3‐/‐ mice had higher urine creatinine excretion than male WT (WT‐Ang II: 734 ± 59 vs PT‐Sirt3‐/‐‐Ang II: 1155 ± 92, µg/mL, P<0.05), but this sex difference was absent in female WT and PT‐Sirt3‐/‐ mice. In general, females had a lower urinary creatinine excretion (UCr) than males. Losartan treatment decreased urinary creatinine excretion in all groups (P<0.05). Similar responses were observed with plasma creatinine levels (SCr), which were higher in PT‐Sirt3‐/‐mice than in WT mice (P<0.05), but without significant sex differences in response to Ang II infusion or losartan treatment. Losartan significantly increased 24 hr urinary potassium and chloride excretion in Ang II‐infused male and female PT‐Sirt3‐/‐ mice (P<0.01). Finally, Ang II‐infused PT‐Sirt3‐/‐ mice showed significant glomerular and renal cortical tubulointerstitial fibrotic responses, compared with WT (P<0.05), without sex differences. Interestingly, losartan treatment did not show decreased fibrotic responses, instead, showed a tendency to higher collagen deposition than in hypertensive PT‐Sirt3‐/‐ mice. In summary and conclusion, male and female PT‐Sirt3‐/‐ mice have lower basal blood pressure, and Ang II‐induced hypertension and renal fibrotic responses are similar in male and female PT‐Sirt3‐/‐ mice without significant sex differences. Our results suggest that AT1a receptors and SIRT3 play important roles in basal blood pressure homeostasis and Ang II‐induced hypertension and glomerular and tubulointerstitial injury in both male and female mice.

Imaging of Corticosteroids in Mouse Kidney Using Mass Spectrometry

Aldosterone regulates renal sodium reabsorption which is important for blood pressure homeostasis. Glucocorticoids may also contribute to this process although this is less well understood. Analysis of steroid hormones and the metabolites in the plasma and urine gives insights into corticosteroid biology but steroid concentrations at a cellular level are largely unknown, and the kidney remains a “black box”. Mass spectrometry imaging (MSI) permits localisation of steroids in histological zones based on regional markers. This approach has been previously applied to localise steroids in brain and testes, and here is applied to kidney. Our aim was to map and quantify glucocorticoids and aldosterone in different histological zones (cortex, medulla) of kidneys from mice receiving different dietary salt, to provide new information relevant to the physiological actions of these hormones.Cryosections kidney from male C57BL6 mouse (age 12 weeks, n=6: dietary salt low 0.03% vs normal 0.3% vs high 3%) were subject to MSI analysis following Girard T reagent derivatisation and α‐cyano‐4‐hydroxycinnamic acid matrix application. Matrix assisted laser desorption/ionisation (MALDI) was used as a sampling method, coupled to Fourier Transform Ion cyclotron mass spectrometry.Ions with m/z 458.3010 (Δppm=0.65), 460.3166 (Δppm=0.65), and 474.2957 (Δppm=1.05) were detected, using MALDI, in renal sections for derivatives of 11‐dehydrocorticosterone, corticosterone and aldosterone respectively. Untargeted evaluation of ions was conducted to find regional markers that would allow definition of kidney histological zones. Heat maps indicated that corticosterone intensity was higher in the inner cortex than the rest of the kidney. In contrast 11‐dehydrocorticosterone, a metabolite produced by the enzymic activity of 11β‐hydroxysteroid dehydrogenase type II, was detected at highest levels in the medulla. The aldosterone signal was equally strong in medulla and outer cortex. Steroid localisation after treatment with different salt intakes indicated that the intensity of the corticosterone signal increases in the outer cortex in kidneys from mice receiving low salt diet, while 11‐dehydrocorticosterone was not affected. The intensity of the aldosterone signal within the kidney was not changed by different salt intakes. Our approach shows that it is feasible to image corticosteroids at 75μm spatial resolution within the kidney. This technology provides new insights into the physiological control of sodium transport by steroids and opens doors to understanding changes in disorders of blood pressure.

Proximal Tubule‐Specific Deletion of Angiotensin II Type 1a Receptors Augments Natriuretic Response to Atrial Natriuretic Peptide via NPRA/cGMP/NO Signaling Pathways in the Kidney

We and others have previously shown that the proximal tubules of the kidney expressed high levels of angiotensin II (Ang II) type 1 (AT1) receptors and atrial natriuretic peptide (ANP) type A receptors (NPRA). In the proximal tubules, Ang II binds and activate AT1 (AT1a) receptors to stimulate proximal tubule Na+reabsorption, whereas ANP binds and activates NPRA receptors to inhibit Ang II‐induced proximal tubule Na+reabsorption. Interactions between Ang II and ANP systems play important counteracting roles in the proximal tubules to control proximal tubule Na+ reabsorption in the kidney and maintain blood pressure homeostasis. It is not known, however, whether the hypotensive and natriuretic responses to ANP are altered by the absence of AT1 (AT1a) receptor‐mediated antinatriuretic action of Ang II in the proximal tubules. The present study used a novel mouse model with proximal tubule‐specific knockout of AT1a receptors in the kidney, PT‐Agtr1a−/−, to test the hypothesis that deletion of AT1a receptors selectively in the proximal tubules augments the hypotensive and natriuretic responses to ANP. Two groups (n=9‐12 per group) of adult male wild‐type and PT‐Agtr1a−/− mice were infused without (time controls) or with ANP via osmotic minipump (10 ng/min, i.p.) continuously for 2 weeks. Basal blood pressure was about 16 ± 3 mmHg lower (P<0.01), fractional proximal tubule Na+ reabsorption was lower (P<0.05), and 24 h urinary Na+ excretion was higher in PT‐Agtr1a−/− mice (P<0.01), compared with wild‐type mice. ANP infusion decreased blood pressure and increased the natriuretic response in PT‐Agtr1a−/− mice further by inhibiting proximal tubule Na+ reabsorption, compared with wild‐type controls (P<0.01). The augmented hypotensive and natriuretic responses to ANP infusion in PT‐Agtr1a−/− mice was associated with increased plasma and kidney cGMP levels (P<0.01), kidney NPRA and NPRC expression (P<0.05), total eNOS and phosphorylated eNOS proteins (P<0.01), and urinary NO excretion (P<0.01), respectively. Taken together, the results of the present study provide further new insights into the important physiological roles for intratubular Ang II/AT1a and ANP/NPRA in the proximal tubules to regulate proximal tubule Na+ reabsorption and help maintain blood pressure homeostasis.

Loss of Clcn6 Alters Expression of Nearby Regulatory Blood Pressure Genes but Does Not Affect High Salt Induced Mortality in Dahl Salt‐Sensitive Rats

Genome‐wide association studies in both humans and Dahl salt‐sensitive (SS) rats have identified the AGTRAP‐PLOD1 locus gene cluster as an area of interest that contains several genes with the ability to regulate blood pressure, including CLCN6, MTHFR, NPPA,and NPPB. We previously demonstrated that a functional knock‐out of Clcn6 on the Dahl SS rat background (SS‐Clcn6) had significantly reduced diastolic blood pressure (BP) compared to WT rats when challenged with a high 4% NaCl (HS) diet to induce hypertension. Increased stroke risk from high blood pressure is well established, and genetic variants, such as those in CLCN6 that reduce BP may also be expected to lower the risk of stroke within this population. Furthermore, a recent paper reported that loss of function mutations in CLCN6 were associated with long‐term survival in a small cohort of sickle cell anemia patients with lower stroke rates. We hypothesized that loss of Clcn6 would delay HS‐induced mortality of Dahl SS rats on a 8% NaCl diet by slowing or preventing lethal cerebrovascular events. However, we observed no significant differences in longevity or neuronal cell death between the SS‐Clcn6 knock‐out and SS‐WT groups. Further assessment led us to examine whether a mutation in Clcn6 could alter mRNA expression of nearby Mthfr, Nppa, and Nppb genes, thereby complicating the genetic phenotype of our knockout animal. We found that on normal salt (NS) diets, renal Mthfr mRNA and protein expression were significantly increased in the SS‐Clcn6 rats, while no differences were observed between WT and knockout rats on a HS diet. MTHFR encodes Methylene tetrahydrofolate reductase (MTHFR), which is involved in reducing homocysteine to methionine, and elevated levels of circulating homocysteine (tHcy) are associated with higher cardiovascular and thromboembolic risk. No significant differences in circulating tHCy between SS‐WT and SS‐Clcn6 (10.63 ± 0.47 vs 10.05 ± 1.12 nM/mL, respectively), were observed on a NS diet; however, there was a trend toward decreased tHcy in SS‐Clcn6 rats on a HS diet (11.85 ± 2.55 vs 6.90 ± 0.40 nM/mL, p=0.08). Genetic ablation of Clcn6 resulted in significant differences in NppamRNA levels in cardiac tissue from SS‐WT and SS‐Clcn6 rat in both normotensive (153.0 ± 23.3 vs 17.61 ±10.67 a.u., p<0.01) and hypertensive (614.9 ± 115.2 vs 153.0 ± 23.3 a.u., p<0.01) conditions. A substantial reduction in NppbmRNA expression in SS‐Clcn6 rats on a NS diet (66.04 ± 4.50 vs 24.01 ± 8.80 a.u., p<0.01) was also found. The observed genetc variances are controversial; while increased Mthfrexpression would be predicted to be protective, reduced Nppaand Nppbexpression could potentially be deleterious and prevent increased vasodilation, natriuresis, and diuresis that should normally occur to compensate for BP increases. Due to the similarity of this genetic locus in humans and rats, more studies are warranted to fully understand how genetic mutations in this cluster may be altering the expression of their neighbors as well as contributing to BP homeostasis.

The Na+/H+ Exchanger 3 in the Intestines and the Proximal Tubule of the Kidney: Localization, Physiological Function, and Key Roles in Angiotensin II-Induced Hypertension.

The sodium (Na+)/hydrogen (H+) exchanger 3 (NHE3) is one of the most important Na+/H+ antiporters in the small intestines of the gastrointestinal tract and the proximal tubules of the kidney. The roles of NHE3 in the regulation of intracellular pH and acid–base balance have been well established in cellular physiology using in vitro techniques. Localized primarily on the apical membranes in small intestines and proximal tubules, the key action of NHE3 is to facilitate the entry of luminal Na+ and the extrusion of intracellular H+ from intestinal and proximal tubule tubular epithelial cells. NHE3 is, directly and indirectly, responsible for absorbing the majority of ingested Na+ from small and large intestines and reabsorbing >50% of filtered Na+ in the proximal tubules of the kidney. However, the roles of NHE3 in the regulation of proximal tubular Na+ transport in the integrative physiological settings and its contributions to the basal blood pressure regulation and angiotensin II (Ang II)-induced hypertension have not been well studied previously due to the lack of suitable animal models. Recently, novel genetically modified mouse models with whole-body, kidney-specific, or proximal tubule-specific deletion of NHE3 have been generated by us and others to determine the critical roles and underlying mechanisms of NHE3 in maintaining basal body salt and fluid balance, blood pressure homeostasis, and the development of Ang II-induced hypertension at the whole-body, kidney, or proximal tubule levels. The objective of this invited article is to review, update, and discuss recent findings on the critical roles of intestinal and proximal tubule NHE3 in maintaining basal blood pressure homeostasis and their potential therapeutic implications in the development of angiotensin II (Ang II)-dependent hypertension.

Angiotensin and Endothelin Receptor Structures With Implications for Signaling Regulation and Pharmacological Targeting.

In conjunction with the endothelin (ET) type A (ETAR) and type B (ETBR) receptors, angiotensin (AT) type 1 (AT1R) and type 2 (AT2R) receptors, are peptide-binding class A G-protein-coupled receptors (GPCRs) acting in a physiologically overlapping context. Angiotensin receptors (ATRs) are involved in regulating cell proliferation, as well as cardiovascular, renal, neurological, and endothelial functions. They are important therapeutic targets for several diseases or pathological conditions, such as hypertrophy, vascular inflammation, atherosclerosis, angiogenesis, and cancer. Endothelin receptors (ETRs) are expressed primarily in blood vessels, but also in the central nervous system or epithelial cells. They regulate blood pressure and cardiovascular homeostasis. Pathogenic conditions associated with ETR dysfunctions include cancer and pulmonary hypertension. While both receptor groups are activated by their respective peptide agonists, pathogenic autoantibodies (auto-Abs) can also activate the AT1R and ETAR accompanied by respective clinical conditions. To date, the exact mechanisms and differences in binding and receptor-activation mediated by auto-Abs as opposed to endogenous ligands are not well understood. Further, several questions regarding signaling regulation in these receptors remain open. In the last decade, several receptor structures in the apo- and ligand-bound states were determined with protein X-ray crystallography using conventional synchrotrons or X-ray Free-Electron Lasers (XFEL). These inactive and active complexes provide detailed information on ligand binding, signal induction or inhibition, as well as signal transduction, which is fundamental for understanding properties of different activity states. They are also supportive in the development of pharmacological strategies against dysfunctions at the receptors or in the associated signaling axis. Here, we summarize current structural information for the AT1R, AT2R, and ETBR to provide an improved molecular understanding.

The Interplay Between COVID-19 and Cardiovascular Disease

Introduction: The emergence of the global COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus, SARS-CoV-2, has created a substantial burden on healthcare systems worldwide. The systemic impacts of COVID-19 infection are severe and broad in their implications, and the cardiovascular system is no exception. Discussion: Patients with a history of cardiovascular disease are at an increased risk for hospitalization and mortality, and COVID-19 infection has now been demonstrated to initiate acute, but serious, episodes of cardiovascular events such as stroke. Considering the rapid spread of COVID-19 across the globe and the inability of healthcare systems to address and adequately respond to the pandemic, therein lies an increased need for understanding the interplay between COVID-19 infection and cardiovascular disease. SARS-CoV-2 relies on binding the angiotensin-converting enzyme-2 (ACE2) receptor to infect host cells, with ACE2 representing a critical regulator of blood pressure homeostasis and proper cardiovascular functioning. Conclusion: Identifying the exact role of ACE2 in COVID-19 infection will have major implications for understanding the disease; therefore, here we have reviewed ACE2’s involvement in the pathogenesis of COVID-19 infection and the resulting end-organ damage. In addition, we have summarized how COVID-19 affects cardiovascular physiology, and how COVID-19 infection can manifest in acute cardiovascular events. Finally, we examine why patients with cardiovascular disease are at an increased risk of succumbing to COVID-19 and what the long-term cardiovascular implications of COVID-19 infection could mean. Relevance: This paper discusses the cardiovascular consequences of the global COVID-19 pandemic.

Angiotensin II and AT1a Receptors in the Proximal Tubules of the Kidney: New Roles in Blood Pressure Control and Hypertension.

Contrary to public perception, hypertension remains one of the most important public health problems in the United States, affecting 46% of adults with increased risk for heart attack, stroke, and kidney diseases. The mechanisms underlying poorly controlled hypertension remain incompletely understood. Recent development in the Cre/LoxP approach to study gain or loss of function of a particular gene has significantly helped advance our new insights into the role of proximal tubule angiotensin II (Ang II) and its AT1 (AT1a) receptors in basal blood pressure control and the development of Ang II-induced hypertension. This novel approach has provided us and others with an important tool to generate novel mouse models with proximal tubule-specific loss (deletion) or gain of the function (overexpression). The objective of this invited review article is to review and discuss recent findings using novel genetically modifying proximal tubule-specific mouse models. These new studies have consistently demonstrated that deletion of AT1 (AT1a) receptors or its direct downstream target Na+/H+ exchanger 3 (NHE3) selectively in the proximal tubules of the kidney lowers basal blood pressure, increases the pressure-natriuresis response, and induces natriuretic responses, whereas overexpression of an intracellular Ang II fusion protein or AT1 (AT1a) receptors selectively in the proximal tubules increases proximal tubule Na+ reabsorption, impairs the pressure-natriuresis response, and elevates blood pressure. Furthermore, the development of Ang II-induced hypertension by systemic Ang II infusion or by proximal tubule-specific overexpression of an intracellular Ang II fusion protein was attenuated in mutant mice with proximal tubule-specific deletion of AT1 (AT1a) receptors or NHE3. Thus, these recent studies provide evidence for and new insights into the important roles of intratubular Ang II via AT1 (AT1a) receptors and NHE3 in the proximal tubules in maintaining basal blood pressure homeostasis and the development of Ang II-induced hypertension.

Natriuretic Peptides and Blood Pressure Homeostasis: Implications for MANP, a Novel Guanylyl Cyclase a Receptor Activator for Hypertension

The heart serves as an endocrine organ producing the hormones atrial natriuretic peptide (ANP) and b-type natriuretic peptide (BNP) which via the guanylyl cyclase A (GC-A) receptor and the second messenger cGMP participate in blood pressure homeostasis under physiologic conditions. Genetic models of the ANP gene or the GCA receptor together with genomic medicine have solidified the concept that both cardiac hormones are fundamental for blood pressure homeostasis and when deficient or disrupted they may contribute to human hypertension. Advances in peptide engineering have led to novel peptide therapeutics including the ANP-analog MANP for human hypertension. Most importantly a first in human study of MANP in essential hypertension has demonstrated its unique properties of aldosterone suppression and blood pressure reduction. Physiology and pharmacology ultimately lead us to innovative peptide-based therapeutics to reduce the burden of cardiovascular disease.

Targeting the ASMase/S1P pathway protects from sortilin-evoked vascular damage in hypertension.

Sortilin has been positively correlated with vascular disorders in humans. No study has yet evaluated the possible direct effect of sortilin on vascular function. We used pharmacological and genetic approaches coupled with study of murine and human samples to unravel the mechanisms recruited by sortilin in the vascular system. Sortilin induced endothelial dysfunction of mesenteric arteries through NADPH oxidase 2 (NOX2) isoform activation, dysfunction that was prevented by knockdown of acid sphingomyelinase (ASMase) or sphingosine kinase 1. In vivo, recombinant sortilin administration induced arterial hypertension in WT mice. In contrast, genetic deletion of sphingosine-1-phosphate receptor 3 (S1P3) and gp91phox/NOX2 resulted in preservation of endothelial function and blood pressure homeostasis after 14 days of systemic sortilin administration. Translating these research findings into the clinical setting, we detected elevated sortilin levels in hypertensive patients with endothelial dysfunction. Furthermore, in a population-based cohort of 270 subjects, we showed increased plasma ASMase activity and increased plasma levels of sortilin, S1P, and soluble NOX2-derived peptide (sNOX2-dp) in hypertensive subjects, and the increase was more pronounced in hypertensive subjects with uncontrolled blood pressure. Our studies reveal what we believe is a previously unrecognized role of sortilin in the impairment of vascular function and in blood pressure homeostasis and suggest the potential of sortilin and its mediators as biomarkers for the prediction of vascular dysfunction and high blood pressure.

Beyond Thermal Sensation: Roles of Transient Receptor Potential Vanilloid Subfamily Member 1 and Spicy Food in Cardiometabolic Diseases

Beyond Thermal Sensation: Roles of Transient Receptor Potential Vanilloid Subfamily Member 1 and Spicy Food in Cardiometabolic Diseases

Genetics association of renin-angiotensin system with atherosclerosis

Angiotensin-converting enzyme (ACE) gene encodes ACE, an enzyme of the renin-angiotensin system (RAS) that plays a significant role in homeostasis and control of blood pressure. It seems that genetic variations can affect ACE function and cause atherosclerosis, one of the most common diseases worldwide, especially in developed countries and one of the leading causes of death in these countries. The presence of ACE insertion/deletion (I/D) affect the function of ACE. This polymorphism can lead to progression of atherosclerosis in some population. Directory of Open Access Journals (DOAJ), Google Scholar and PubMed of the most common diseases worldwide. Additionally, EBSCO and Web of Science have been searched. In this review, we studied the effects of ACE I/D polymorphism in various populations and its influence on the risk of onset and progression of atherosclerosis. Depending on the population and the area under study, polymorphisms can contribute to the risk of disease.

Fluorescence detection of the human angiotensinogen protein by the G-quadruplex aptamer.

Noncanonical G-quadruplex nucleic acid structures can be used as probes in biosensors for the detection of metal ions, proteins and nucleic acids. Angiotensinogen (AGT) is a glycosylated globulin found in serum, which can regulate blood pressure and body fluid homeostasis. AGT is an important part of the renin-angiotensin system (RAS) and can be potentially used as a biomarker of diseases with RAS alterations. G-quadruplex based biosensors can detect targets with high accuracy and speed and low cost. Employing the magnetic bead enrichment method we constructed a reliable and efficient fluorescent biosensor platform for G-quadruplex based detection of the human AGT protein. The primary antibody in our biosensor is recognized by fluorescently labeled secondary antibodies, which leads to the detection of AGT captured by the G-quadruplex aptamer coupled magnetic beads. This G-quadruplex based fluorescent biosensor designed with a detection limit of 5 × 10-5 mg mL-1 was used for the successful detection of AGT at the cellular level. Our G-quadruplex based fluorescent biosensor will contribute to the more reliable and efficient detection of AGT.

Impact Bilateral Carotid Body Tumor Resection in the Carotid Baroreceptor Function

Baroreflexes are responsible for maintaining blood pressure (BP) homeostasis and avoiding volatile hemodynamic changes. The baroreflex arc is a negative feedback loop that acts as a buffer for BP and heart rate during postural changes, physical or emotional stress. When some afferent component of this arc fails, prompting changes in the function of the baroreceptors, it is known as baroreceptor failure (BRF). Four forms of presentation have been described: hypertensive crisis, volatile hypertension, and orthostatic malignant vagotonia.