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Circulation Research Jan 2024T cells are central to the immune responses contributing to hypertension. LGMN (legumain) is highly expressed in T cells; however, its role in the pathogenesis of...
BACKGROUND
T cells are central to the immune responses contributing to hypertension. LGMN (legumain) is highly expressed in T cells; however, its role in the pathogenesis of hypertension remains unclear.
METHODS
Peripheral blood samples were collected from patients with hypertension, and cluster of differentiation (CD)4+ T cells were sorted for gene expression and Western blotting analysis. TLGMNKO (T cell-specific LGMN-knockout) mice (Lgmn/CD4), regulatory T cell (Treg)-specific LGMN-knockout mice (Lgmn/Foxp3), and RR-11a (LGMN inhibitor)-treated C57BL/6 mice were infused with Ang II (angiotensin II) or deoxycorticosterone acetate/salt to establish hypertensive animal models. Flow cytometry, 4-dimensional label-free proteomics, coimmunoprecipitation, Treg suppression, and in vivo Treg depletion or adoptive transfer were used to delineate the functional importance of T-cell LGMN in hypertension development.
RESULTS
LGMN mRNA expression was increased in CD4+ T cells isolated from hypertensive patients and mice, was positively correlated with both systolic and diastolic blood pressure, and was negatively correlated with serum IL (interleukin)-10 levels. TLGMNKO mice exhibited reduced Ang II-induced or deoxycorticosterone acetate/salt-induced hypertension and target organ damage relative to wild-type (WT) mice. Genetic and pharmacological inhibition of LGMN blocked Ang II-induced or deoxycorticosterone acetate/salt-induced immunoinhibitory Treg reduction in the kidneys and blood. Anti-CD25 antibody depletion of Tregs abolished the protective effects against Ang II-induced hypertension in TLGMNKO mice, and LGMN deletion in Tregs prevented Ang II-induced hypertension in mice. Mechanistically, endogenous LGMN impaired Treg differentiation and function by directly interacting with and facilitating the degradation of TRAF6 (tumor necrosis factor receptor-associated factor 6) via chaperone-mediated autophagy, thereby inhibiting NF-κB (nuclear factor kappa B) activation. Adoptive transfer of LGMN-deficient Tregs reversed Ang II-induced hypertension, whereas depletion of TRAF6 in LGMN-deficient Tregs blocked the protective effects.
CONCLUSIONS
LGMN deficiency in T cells prevents hypertension and its complications by promoting Treg differentiation and function. Specifically targeting LGMN in Tregs may be an innovative approach for hypertension treatment.
Topics: Animals; Humans; Mice; Acetates; Angiotensin II; CD4-Positive T-Lymphocytes; Desoxycorticosterone; Hypertension; Mice, Inbred C57BL; Mice, Knockout; T-Lymphocytes, Regulatory; TNF Receptor-Associated Factor 6
PubMed: 38047378
DOI: 10.1161/CIRCRESAHA.123.322835 -
Journal of Veterinary Internal Medicine Mar 2023Primary hypoadrenocorticism (PH) is rare in cats and knowledge about treatment is sparse.
BACKGROUND
Primary hypoadrenocorticism (PH) is rare in cats and knowledge about treatment is sparse.
OBJECTIVE
To describe cats with PH with a focus on long-term treatment.
ANIMALS
Eleven cats with naturally occurring PH.
METHODS
Descriptive case series with data on signalment, clinicopathological findings, adrenal width, and doses of desoxycorticosterone pivalate (DOCP) and prednisolone during a follow-up period of >12 months.
RESULTS
Cats ranged from 2 to 10 years (median 6.5); 6 cats were British Shorthair. Most common signs were reduced general condition and lethargy, anorexia, dehydration, obstipation, weakness, weight loss, and hypothermia. Adrenal glands on ultrasonography were judged small in 6. Eight cats could be followed for 14 to 70 months (median: 28). Two were started on DOCP doses ≥2.2 mg/kg (2.2; 2.5) and 6 < 2.2 mg/kg (1.5-2.0 mg/kg, median 1.8) q28 days. Both high-dose cats and 4 low-dose cats needed a dose increase. Desoxycorticosterone pivalate and prednisolone doses at the end of the follow-up period were 1.3 to 3.0 mg/kg (median: 2.3) and 0.08 to 0.5 mg/kg/day (median: 0.3), respectively.
CONCLUSIONS AND CLINICAL IMPORTANCE
Desoxycorticosterone pivalate and prednisolone requirements in cats were higher than what is currently used in dogs; thus, a DOCP starting dose of 2.2 mg/kg q28 days and a prednisolone maintenance dose of 0.3 mg/kg/day titrated to the individual need seems warranted. Small adrenal glands (width < 2.7 mm) on ultrasonography in a cat suspected of hypoadrenocorticism can be suggestive of the disease. The apparent predilection of British Shorthaired cats for PH should be further evaluated.
Topics: Cats; Animals; Dogs; Prednisolone; Dog Diseases; Adrenal Insufficiency; Desoxycorticosterone; Addison Disease; Cat Diseases
PubMed: 36809682
DOI: 10.1111/jvim.16658 -
Current Hypertension Reports Apr 2017Hypertension is a multifaceted disease that is involved in ∼40% of cardiovascular mortalities and is the result of both genetic and environmental factors. Because of... (Review)
Review
Hypertension is a multifaceted disease that is involved in ∼40% of cardiovascular mortalities and is the result of both genetic and environmental factors. Because of its complexity, hypertension has been studied by using various models and approaches, each of which tends to focus on individual organs or tissues to isolate the most critical and treatable causes of hypertension and the related damage to end-organs. Animal models of hypertension have ranged from Goldblatt's kidney clip models in which the origin of the disease is clearly renal to animals that spontaneously develop hypertension either through targeted genetic manipulations, such as the TGR(mRen2)27, or selective breeding resulting in more enigmatic origins, as exemplified by the spontaneously hypertensive rat (SHR). These two genetically derived models simulate the less-common human primary hypertension in which research has been able to define a Mendelian linkage. Several models are more neurogenic or endocrine in nature and illustrate that crosstalk between the nervous system and hormones can cause a significant rise in blood pressure (BP). This review will examine one of these neurogenic models of hypertension, i.e., the deoxycorticosterone acetate (DOCA), reduced renal mass, and high-salt diet (DOCA-salt) rodent model, one of the most common experimental models used today. Although the DOCA-salt model is mainly believed to be neurogenic and has been shown to impact the central and peripheral nervous systems, it also significantly involves many other body organs.
Topics: Animals; Blood Pressure; Desoxycorticosterone Acetate; Humans; Hypertension; Kidney; Sodium Chloride, Dietary
PubMed: 28353076
DOI: 10.1007/s11906-017-0731-4 -
Journal of Veterinary Internal Medicine Jul 2021Desoxycorticosterone pivalate (DOCP) is a commonly used mineralocorticoid replacement for dogs with primary hypoadrenocorticism (HA), but manufacturer-recommended dosing...
BACKGROUND
Desoxycorticosterone pivalate (DOCP) is a commonly used mineralocorticoid replacement for dogs with primary hypoadrenocorticism (HA), but manufacturer-recommended dosing protocols can be cost-prohibitive. Recent reports also have raised concerns that label dose protocols could be excessive.
OBJECTIVE
To investigate the relative efficacy and adverse effects of 2 DOCP dosages in dogs with primary glucocorticoid and mineralocorticoid deficient HA.
ANIMALS
Thirty-seven dogs, including 19 test population dogs and 18 controls.
METHODS
Randomized controlled double-blinded clinical trial. Dogs with newly diagnosed primary HA were assigned to standard (2.2 mg/kg q30d, control population) or low-dose (1.1 mg/kg q30d, test population) DOCP treatment. Clinical and laboratory variables were assessed 10 to 14 days and approximately 30 days after each DOCP treatment for 90 days.
RESULTS
Mean serum sodium to potassium ratios at reevaluations were ≥32 in both populations throughout the study. No dog developed electrolyte abnormalities warranting medical treatment, although hypokalemia occurred on at least 1 occasion in 9 controls and 6 test population dogs. Urine specific gravities (median, interquartile range) were lower in control dogs (1.022, 1.016-1.029) as compared to test population dogs (1.033, 1.023-1.039; P = .006). Plasma renin activity was overly suppressed on 84 of 104 (80.8%) assessments in control dogs whereas increased renin activity occurred on 23 of 112 (20.5%) assessments in test population dogs.
CONCLUSIONS AND CLINICAL IMPORTANCE
Low-dose DOCP protocols appear to be safe and effective for treatment of HA in most dogs. Standard-dose protocols are more likely to result in biochemical evidence of overtreatment.
Topics: Adrenal Insufficiency; Animals; Desoxycorticosterone; Dog Diseases; Dogs; Mineralocorticoids
PubMed: 34114259
DOI: 10.1111/jvim.16195 -
Critical Care (London, England) Nov 2022Steroid profiles in combination with a corticotropin stimulation test provide information about steroidogenesis and its functional reserves in critically ill patients. (Randomized Controlled Trial)
Randomized Controlled Trial
RATIONALE
Steroid profiles in combination with a corticotropin stimulation test provide information about steroidogenesis and its functional reserves in critically ill patients.
OBJECTIVES
We investigated whether steroid profiles before and after corticotropin stimulation can predict the risk of in-hospital death in sepsis.
METHODS
An exploratory data analysis of a double blind, randomized trial in sepsis (HYPRESS [HYdrocortisone for PRevention of Septic Shock]) was performed. The trial included adult patients with sepsis who were not in shock and were randomly assigned to placebo or hydrocortisone treatment. Corticotropin tests were performed in patients prior to randomization and in healthy subjects. Cortisol and precursors of glucocorticoids (17-OH-progesterone, 11-desoxycortisol) and mineralocorticoids (11-desoxycorticosterone, corticosterone) were analyzed using the multi-analyte stable isotope dilution method (LC-MS/MS). Measurement results from healthy subjects were used to determine reference ranges, and those from placebo patients to predict in-hospital mortality.
MEASUREMENTS AND MAIN RESULTS
Corticotropin tests from 180 patients and 20 volunteers were included. Compared to healthy subjects, patients with sepsis had elevated levels of 11-desoxycorticosterone and 11-desoxycortisol, consistent with activation of both glucocorticoid and mineralocorticoid pathways. After stimulation with corticotropin, the cortisol response was subnormal in 12% and the corticosterone response in 50% of sepsis patients. In placebo patients (n = 90), a corticotropin-stimulated cortisol-to-corticosterone ratio > 32.2 predicted in-hospital mortality (AUC 0.8 CI 0.70-0.88; sensitivity 83%; and specificity 78%). This ratio also predicted risk of shock development and 90-day mortality.
CONCLUSIONS
In this exploratory analysis, we found that in sepsis mineralocorticoid steroidogenesis was more frequently impaired than glucocorticoid steroidogenesis. The corticotropin-stimulated cortisol-to-corticosterone ratio predicts the risk of in-hospital death. Trial registration Clinical trial registered with www.
CLINICALTRIALS
gov Identifier: NCT00670254. Registered 1 May 2008, https://clinicaltrials.gov/ct2/show/NCT00670254 .
Topics: Adult; Humans; Adrenocorticotropic Hormone; Hydrocortisone; Hospital Mortality; Glucocorticoids; Mineralocorticoids; Corticosterone; Cortodoxone; Chromatography, Liquid; Tandem Mass Spectrometry; Sepsis; Shock, Septic; Desoxycorticosterone
PubMed: 36345013
DOI: 10.1186/s13054-022-04224-5 -
The Journal of Steroid Biochemistry and... Jun 2016GABAA receptor modulating steroid antagonists (GAMSA) selectively inhibit neurosteroid-mediated enhancement of GABA-evoked currents at the GABAA receptor.... (Review)
Review
GABAA receptor modulating steroid antagonists (GAMSA) selectively inhibit neurosteroid-mediated enhancement of GABA-evoked currents at the GABAA receptor. 3α-hydroxy-neurosteroids, notably allopregnanolone and tetrahydrodeoxycorticosterone (THDOC), potentiate GABAA receptor-mediated currents. On the contrary, various 3β-hydroxy-steroids antagonize this positive neurosteroid-mediated modulation. Importantly, GAMSAs are specific antagonists of the positive neurosteroid-modulation of the receptor and do not inhibit GABA-evoked currents. Allopregnanolone and THDOC have both negative and positive actions. Allopregnanolone can impair encoding/consolidation and retrieval of memories. Chronic administration of a physiological allopregnanolone concentration reduces cognition in mice models of Alzheimer's disease. In humans an allopregnanolone challenge impairs episodic memory and in hepatic encephalopathy cognitive deficits are accompanied by increased brain ammonia and allopregnanolone. Hippocampal slices react in vitro to ammonia by allopregnanolone synthesis in CA1 neurons, which blocks long-term potentiation (LTP). Thus, allopregnanolone may impair learning and memory by interfering with hippocampal LTP. Contrary, pharmacological treatment with allopregnanolone can promote neurogenesis and positively influence learning and memory of trace eye-blink conditioning in mice. In rat the GAMSA UC1011 inhibits an allopregnanolone-induced learning impairment and the GAMSA GR3027 restores learning and motor coordination in rats with hepatic encephalopathy. In addition, the GAMSA isoallopregnanolone antagonizes allopregnanolone-induced anesthesia in rats, and in humans it antagonizes allopregnanolone-induced sedation and reductions in saccadic eye velocity. 17PA is also an effective GAMSA in vivo, as it antagonizes allopregnanolone-induced anesthesia and spinal analgesia in rats. In vitro the allopregnanolone/THDOC-increased GABA-mediated GABAA receptor activity is antagonized by isoallopregnanolone, UC1011, GR3027 and 17PA, while the effect of GABA itself is not affected.
Topics: Animals; Desoxycorticosterone; Evoked Potentials; GABA-A Receptor Antagonists; Humans; Learning; Memory; Pregnanolone; Receptors, GABA-A; Saccades
PubMed: 26523675
DOI: 10.1016/j.jsbmb.2015.10.019 -
The Journal of Clinical Endocrinology... Oct 2023There is no early, first-trimester risk estimation available to predict later (gestational week 24-28) gestational diabetes mellitus (GDM); however, it would be...
CONTEXT
There is no early, first-trimester risk estimation available to predict later (gestational week 24-28) gestational diabetes mellitus (GDM); however, it would be beneficial to start an early treatment to prevent the development of complications.
OBJECTIVE
We aimed to identify early, first-trimester prediction markers for GDM.
METHODS
The present case-control study is based on the study cohort of a Hungarian biobank containing biological samples and follow-up data from 2545 pregnant women. Oxidative-nitrative stress-related parameters, steroid hormone, and metabolite levels were measured in the serum/plasma samples collected at the end of the first trimester from 55 randomly selected control and 55 women who developed GDM later.
RESULTS
Pregnant women who developed GDM later during the pregnancy were older and had higher body mass index. The following parameters showed higher concentration in their serum/plasma samples: fructosamine, total antioxidant capacity, testosterone, cortisone, 21-deoxycortisol; soluble urokinase plasminogen activator receptor, dehydroepiandrosterone sulfate, dihydrotestosterone, cortisol, and 11-deoxycorticosterone levels were lower. Analyzing these variables using a forward stepwise multivariate logistic regression model, we established a GDM prediction model with a specificity of 96.6% and sensitivity of 97.5% (included variables: fructosamine, cortisol, cortisone, 11-deoxycorticosterone, SuPAR).
CONCLUSION
Based on these measurements, we accurately predict the development of later-onset GDM (24th-28th weeks of pregnancy). Early risk estimation provides the opportunity for targeted prevention and the timely treatment of GDM. Prevention and slowing the progression of GDM result in a lower lifelong metabolic risk for both mother and offspring.
Topics: Female; Humans; Pregnancy; Cortisone; Desoxycorticosterone; Diabetes, Gestational; Fructosamine; Hydrocortisone; Pregnancy Trimester, First; Case-Control Studies
PubMed: 37247379
DOI: 10.1210/clinem/dgad301 -
Psychoneuroendocrinology Nov 2020Neuroactive steroids (NAS) are derivatives of cholesterol or steroidal precursors made in the gonads, adrenal gland, placenta and brain. We characterized longitudinal...
Longitudinal proneuroactive and neuroactive steroid profiles in medication-free women with, without and at-risk for perinatal depression: A liquid chromatography-tandem mass spectrometry analysis.
BACKGROUND
Neuroactive steroids (NAS) are derivatives of cholesterol or steroidal precursors made in the gonads, adrenal gland, placenta and brain. We characterized longitudinal plasma proneuroactive and NAS in healthy perinatal comparison women (HPCW), women at-risk for perinatal depression (AR-PND), and women with PND with/without comorbid anxiety. We hypothesized that AR-PND women who either did or did not go on to develop PND would have elevated NAS concentrations as compared to HPCW and that NAS would be correlated to depressive and anxiety symptoms.
METHODS
A prospective cohort study evaluated 75 medication-free perinatal women (HPCW, n = 30; AR-PND, n = 19; PND, n = 26). Standardized depression and anxiety assessments and blood samples were completed across 5 visits. Structured Clinical Interviews for DSM-IV TR Disorders were administered at study entry and exit. Plasma pregnenolone, progesterone, 5α- and 5β-dihydroprogesterone, pregnanolone, allopregnanolone, deoxycorticosterone and tetrahydrodeoxycorticosterone were quantified by liquid chromatography-tandem mass spectrometry. Longitudinal relationships between risk-group, depression and anxiety symptoms, and NAS concentrations were analyzed using generalized estimating equations to control for repeated measures correlations.
RESULTS
Perinatal 5α-dihydroprogesterone, 5β-dihydroprogesterone, allopregnanolone, deoxycorticosterone, and tetrahydrodeoxycorticosterone concentrations were higher in AR-PND and PND women compared to HPCW (β = 3.57 ± 1.40 and β = 2.11 ± 1.12, p = 0.03; β = 0.18 ± 0.06 and β = 0.03 ± 0.05, p = 0.02; β = 1.06 ± 0.42 and β = 1.19 ± 0.47, p = 0.01; β = 0.17 ± 0.07 and β = 0.11 ± 0.06, p = 0.05; β = 0.03 ± 0.01 and β = 0.03 ± 0.01, p = 0.05, respectively). Perinatal allopregnanolone, 5α-dihydroprogesterone and tetrahydrodeoxycorticosterone were positively associated with HAM-D (all p < 0.02). HAM-A was positively associated with 5α- and 5β-dihydroprogesterone, pregnanolone, allopregnanolone, deoxycorticosterone and tetrahydrodeoxycorticosterone (all p < 0.05). A history of depression was associated with increased 5α-dihydroprogesterone (2.20 ± 1.09, p = 0.05), deoxycorticosterone (0.13 ± 0.06, p = 0.03) and tetrahydrodeoxycorticosterone (0.03 ± 0.01, p = 0.02).
CONCLUSION
To our knowledge, this study represents the largest prospective study of 5-α and 5-β reductase products of progesterone and deoxycorticosterone in HPCW and women AR-PND. Data suggest that PND is associated with both a reduction of progesterone to 5β-dihydroprogesterone, 5α-dihydroprogesterone, and allopregnanolone, and the 21-hydroxylation to deoxycorticosterone and tetrahydrodeoxycorticosterone. The shift towards 5α-dihydroprogesterone, deoxycorticosterone and tetrahydrodeoxycorticosterone was associated with a history of depression, a significant risk factor for PND.
Topics: 20-alpha-Dihydroprogesterone; Adult; Anxiety; Chromatography, Liquid; Depression; Depression, Postpartum; Depressive Disorder; Desoxycorticosterone; Female; Humans; Longitudinal Studies; Neurosteroids; Parturition; Pregnancy; Pregnanolone; Pregnenolone; Prenatal Care; Progesterone; Prospective Studies; Risk Factors; Tandem Mass Spectrometry
PubMed: 32828068
DOI: 10.1016/j.psyneuen.2020.104827 -
Journal of the American Heart... Jul 2023Background Different T-lymphocyte subsets, including CD1d-dependent natural killer T (NKT) cells, play distinct roles in hypertension, highlighting the importance of...
Background Different T-lymphocyte subsets, including CD1d-dependent natural killer T (NKT) cells, play distinct roles in hypertension, highlighting the importance of identifying key immune cells for its treatment. This study aimed to determine the unknown effects of CD1d-dependent NKT cells on hypertension and vascular injury. Methods and Results Hypertension models were induced in male CD1d knockout (CD1dko), wild-type, and adoptive bone marrow transfer mice by angiotensin II (Ang II) or deoxycorticosterone acetate salt. Blood pressure was measured by the tail-cuff system and radiotelemetry. Vascular injury was assessed by histologic studies or aortic ring assay. Inflammation was detected by flow cytometry, quantitative real-time polymerase chain reaction, or ELISA. Results showed that Ang II infusion significantly reduced CD1d expression and NKT cell numbers in the aorta of mice. CD1dko mice exhibited worsened blood pressure elevation, vascular injury, and inflammatory response induced by Ang II or deoxycorticosterone acetate salt. However, these effects were markedly reversed in wild-type mice treated with NKT cell-specific activator. Adoptive transfer of CD1dko bone marrow cells to wild-type mice also significantly worsened Ang II-induced responses. Mechanistically, CD1dko increased Ang II-induced interleukin-6 production and activated signal transducer and activator of transcription 3 and orphan nuclear receptor γ, subsequently inducing interleukin-17A production. Neutralizing interleukin-17A partially reversed Ang II-induced hypertension and vascular injury in CD1dko mice. In addition, levels of NKT cells were lower in the blood of patients with hypertension (n=57) compared with normotensive individuals (n=87). Conclusions These findings reveal a previously unknown role for CD1d-dependent NKT cells in hypertension and vascular injury, indicating that NKT cell activation could be a promising therapeutic target for hypertension.
Topics: Animals; Male; Mice; Acetates; Desoxycorticosterone; Hypertension; Interleukin-17; Mice, Inbred C57BL; Mice, Knockout; Natural Killer T-Cells; Vascular System Injuries
PubMed: 37382154
DOI: 10.1161/JAHA.122.029179 -
Hypertension (Dallas, Tex. : 1979) Nov 2022GPCRs (G protein-coupled receptors) are implicated in blood pressure (BP) and fluid intake regulation. There is a developing concept that these effects are mediated by...
BACKGROUND
GPCRs (G protein-coupled receptors) are implicated in blood pressure (BP) and fluid intake regulation. There is a developing concept that these effects are mediated by both canonical G protein signaling and noncanonical β-arrestin mediated signaling, but the contributions of each remain largely unexplored. Here, we hypothesized that β-arrestin contributes to fluid homeostasis and blood pressure (BP) regulation in deoxycorticosterone acetate (DOCA) salt hypertension, a prototypical model of salt-sensitive hypertension.
METHODS
Global β-arrestin1 () and β-arrestin2 () knockout mice were employed to evaluate drinking behavior, and BP was evaluated in -knockout mice. Age- and sex-matched C57BL/6 mice served as controls. We measured intake of water and different sodium chloride solutions and BP employing a 2-bottle choice paradigm with and without DOCA.
RESULTS
Without DOCA (baseline), -knockout mice exhibited a significant elevation in saline intake with no change in water intake. With DOCA treatment, -knockout mice exhibited a significant increase in both saline and water intake. Although -knockout mice exhibited hypernatremia at baseline conditions, we did not find significant changes in total body sodium stores or sodium palatability. In a separate cohort, BP was measured via telemetry in -knockout and C57BL/6 mice with and without DOCA. -knockout did not exhibit significant differences in BP before DOCA treatment when provided water alone, or when provided a choice of water and saline. However, -knockout exhibited an increased pressor response to DOCA-salt.
CONCLUSIONS
These findings suggest that in salt-sensitive hypertension, ARRB2, but not ARRB1 (β-arrestin 1), might counterbalance the canonical signaling of GPCRs.
Topics: Animals; Mice; Blood Pressure; Desoxycorticosterone Acetate; beta-Arrestin 2; Mice, Inbred C57BL; Hypertension; Sodium Chloride, Dietary; Sodium Chloride; Sodium; beta-Arrestins; Mice, Knockout; Homeostasis; Water; Desoxycorticosterone
PubMed: 36215165
DOI: 10.1161/HYPERTENSIONAHA.122.19863