RÉSUMÉ
Hypertension affects one-third of the adult population worldwide, with primary aldosteronism (PA) accounting for at least 5-10% of these cases. The aldosterone synthase enzyme (CYP11B2) plays a pivotal role in PA manifestation, as increased expression of CYP11B2 leads to excess aldosterone synthesis. Physiological expression of CYP11B2 in humans is normally limited to cells of the adrenal zona glomerulosa under tight homeostatic regulation. In PA, however, there are CYP11B2-positive lesions in the adrenal cortex that autonomously secrete aldosterone, highlighting the dysregulation of adrenal cortex zonation and function as a key aspect of PA pathogenesis. Thus, this review aims to summarize the development of the adrenal glands, the key regulators of adrenal cortex homeostasis, and the dysregulation of this homeostasis. It also discusses the development of CYP11B2 inhibitors for therapeutic use in patients with hypertension, as well as the current knowledge of the effects of CYP11B2 inhibition on adrenal cortex homeostasis and cell fate. Understanding the control of adrenal cell fate may offer valuable insights into both the pathogenesis of PA and the development of alternative treatment approaches for PA.
Sujet(s)
Glandes surrénales , Aldostérone , Cytochrome P-450 CYP11B2 , Hyperaldostéronisme , Humains , Aldostérone/métabolisme , Aldostérone/biosynthèse , Cytochrome P-450 CYP11B2/métabolisme , Hyperaldostéronisme/métabolisme , Hyperaldostéronisme/anatomopathologie , Glandes surrénales/métabolisme , Animaux , Cortex surrénal/métabolisme , Cortex surrénal/cytologie , Hypertension artérielle/métabolisme , Hypertension artérielle/anatomopathologie , Zone glomérulée/métabolisme , Différenciation cellulaire , HoméostasieRÉSUMÉ
Glaucoma, a leading cause of blindness worldwide, encompasses a group of pathological conditions affecting the optic nerve and is characterized by progressive retinal ganglion cell loss, cupping of the optic nerve head, and distinct visual field defects. While elevated intraocular pressure (IOP) is the main risk factor for glaucoma, many patients do not have elevated IOP. Consequently, other risk factors, such as ocular blood flow abnormalities and immunological factors, have been implicated in its pathophysiology. Traditional therapeutic strategies primarily aim to reduce IOP, but there is growing interest in developing novel treatment approaches to improve disease management and reduce the high rates of severe visual impairment. In this context, targeting the ocular renin-angiotensin-aldosterone system (RAAS) has been found as a potential curative strategy. The RAAS contributes to glaucoma development through key effectors such as prorenin, angiotensin II, and aldosterone. Recent evidence has highlighted the potential of using RAAS modulators to combat glaucoma, yielding encouraging results. Our study aims to explore the molecular pathways linking the ocular RAAS and glaucoma, summarizing recent advances that elucidate the role of the RAAS in triggering oxidative stress, inflammation, and remodelling in the pathogenesis of glaucoma. Additionally, we will present emerging therapeutic approaches that utilize RAAS modulators and antioxidants to slow the progression of glaucoma.
Sujet(s)
Glaucome , Système rénine-angiotensine , Animaux , Humains , Glaucome/métabolisme , Glaucome/thérapie , Pression intraoculaire , Stress oxydatif , Transduction du signal , Aldostérone/métabolismeRÉSUMÉ
Aldosterone-producing adenoma is a subtype of primary aldosteronism. Recent advancements in multi-omics research have led to significant progress in understanding primary aldosteronism at the genetic level. Among the various genes associated with the development of aldosterone-producing adenomas, the KCNJ5 (potassium inwardly rectifying channel, subfamily J, member 5) gene has received considerable attention due to its prevalence as the most common somatic mutation gene in primary aldosteronism. This paper aims to integrate the existing evidence on the involvement of KCNJ5 gene in the pathogenesis of aldosterone-producing adenomas, to enhance the understanding of the underlying mechanisms of aldosterone-producing adenomas from the perspective of genetics, and to provide novel insights for the clinical diagnosis and treatment of aldosterone-producing adenomas.
Sujet(s)
Tumeurs corticosurrénaliennes , Adénome corticosurrénalien , Aldostérone , Canaux potassiques rectifiants entrants couplés aux protéines G , Hyperaldostéronisme , Humains , Canaux potassiques rectifiants entrants couplés aux protéines G/génétique , Canaux potassiques rectifiants entrants couplés aux protéines G/métabolisme , Aldostérone/métabolisme , Aldostérone/biosynthèse , Hyperaldostéronisme/génétique , Hyperaldostéronisme/métabolisme , Adénome corticosurrénalien/génétique , Adénome corticosurrénalien/métabolisme , Tumeurs corticosurrénaliennes/génétique , Tumeurs corticosurrénaliennes/métabolisme , Adénomes/génétique , Adénomes/métabolisme , MutationRÉSUMÉ
Epithelial Na+ channels (ENaCs) are activated by proteolysis of the α and γ subunits at specific sites flanking embedded inhibitory tracts. To examine the role of α subunit proteolysis in channel activation in vivo, we generated mice lacking the distal furin cleavage site in the α subunit (αF2M mice). On a normal Na+ control diet, no differences in ENaC protein abundance in kidney or distal colon were noted between wild-type (WT) and αF2M mice. Patch-clamp analyses revealed similar levels of ENaC activity in kidney tubules, while no physiologically relevant differences in blood chemistry or aldosterone levels were detected. Male αF2M mice did exhibit diminished ENaC activity in the distal colon, as measured by amiloride-sensitive short-circuit current (ISC). Following dietary Na+ restriction, WT and αF2M mice had similar natriuretic and colonic ISC responses to amiloride. However, single-channel activity was significantly lower in kidney tubules from Na+-restricted αF2M mice compared with WT littermates. ENaC α and γ subunit expression in kidney and distal colon were also enhanced in Na+-restricted αF2M vs. WT mice, in association with higher aldosterone levels. These data provide evidence that disrupting α subunit proteolysis impairs ENaC activity in vivo, requiring compensation in response to Na+ restriction. KEY POINTS: The epithelial Na+ channel (ENaC) is activated by proteolytic cleavage in vitro, but key questions regarding the role of ENaC proteolysis in terms of whole-animal physiology remain to be addressed. We studied the in vivo importance of this mechanism by generating a mouse model with a genetic disruption to a key cleavage site in the ENaC's α subunit (αF2M mice). We found that αF2M mice did not exhibit a physiologically relevant phenotype under normal dietary conditions, but have impaired ENaC activation (channel open probability) in the kidney during salt restriction. ENaC function at the organ level was preserved in salt-restricted αF2M mice, but this was associated with higher aldosterone levels and increased expression of ENaC subunits, suggesting compensation was required to maintain homeostasis. These results provide the first evidence that ENaC α subunit proteolysis is a key regulator of channel activity in vivo.
Sujet(s)
Canaux sodium épithéliaux , Furine , Animaux , Canaux sodium épithéliaux/métabolisme , Canaux sodium épithéliaux/génétique , Souris , Mâle , Furine/métabolisme , Furine/génétique , Sodium/métabolisme , Côlon/métabolisme , Souris de lignée C57BL , Aldostérone/métabolisme , Régime pauvre en selRÉSUMÉ
OBJECTIVE: Previous studies indicate a possible bidirectional stimulatory relationship between parathyroid hormone (PTH) and adrenocortical hormones, but the pattern of adrenocortical secretion in hypoparathyroidism is unknown. We aimed to characterize the adrenocortical secretion in patients with postsurgical hypoparathyroidism, and whether continuous subcutaneous PTH (1-34) infusion alters secretion patterns. DESIGN: Crossover interventional study. METHODS: We recruited 10 patients with postsurgical hypoparathyroidism with very low PTH levels on stable treatment with active vitamin D and calcium. Cortisol, cortisone, and aldosterone levels were measured in microdialysate from subcutaneous tissue over 24â h, before and during continuous subcutaneous PTH (1-34) infusion. Cortisol was also assayed in serum, saliva, and urine, and aldosterone and ACTH in serum and plasma, respectively. Ten patients with primary hyperparathyroidism and 10 healthy volunteers matched for sex and age served as controls. RESULTS: Hypoparathyroid patients displayed both ultradian and circadian rhythmicity for tissue cortisol, cortisone, and aldosterone. Tissue aldosterone and cortisone levels were significantly lower in hypoparathyroid patients than in healthy controls, with no difference in tissue cortisol, but a higher cortisol to cortisone ratio. Treatment with PTH (1-34) increased tissue levels of aldosterone, cortisol, and cortisone and reduced the ratio of cortisol to cortisone. CONCLUSION: Adrenocortical hormone levels are reduced in postsurgical hypoparathyroidism, and partly restored by short-term continuous subcutaneous PTH (1-34) therapy. CLINICAL TRIAL REGISTRATION NUMBER: NCT02986607.
Sujet(s)
Aldostérone , Rythme circadien , Études croisées , Hydrocortisone , Hypoparathyroïdie , Hormone parathyroïdienne , Humains , Femelle , Mâle , Adulte d'âge moyen , Hypoparathyroïdie/traitement médicamenteux , Hypoparathyroïdie/sang , Rythme circadien/physiologie , Hormone parathyroïdienne/sang , Adulte , Hydrocortisone/sang , Aldostérone/sang , Aldostérone/métabolisme , Sujet âgé , Cortisone/sang , Cortisone/métabolisme , Hormones corticosurrénaliennes/usage thérapeutiqueRÉSUMÉ
Primary aldosteronism (PA) is a common cause of secondary hypertension. Adrenalectomy is an effective treatment for unilateral PA, particularly aldosterone-producing adenoma (APA), resulting in improvements in biochemical parameters and blood pressure in the vast majority of patients. The article provides a comprehensive overview of PA, focusing on the outcomes of adrenalectomy for PA and the factors that may suggest prognostic implications. Analysis of the outcome of different PA patients undergoing adrenalectomy in terms of preoperative factors, vascular and adipose conditions, type of pathology, and somatic variants. In addition, it is recommended to use the histopathology of primary aldosteronism (HISTALDO) consensus to classify the patient's pathological type, with classical and nonclassical pathological types showing a different prognosis and possibly being associated with an unresected contralateral adrenal gland. The primary aldosteronism surgical outcome (PASO) consensus sets uniform standards for postoperative outcomes in unilateral PA, but its setting of thresholds remains controversial. Partial adrenalectomy shows similar surgical results and fewer postoperative complications than total adrenalectomy, but there is a risk of missing the true source of abnormal aldosterone secretion. Steroid profiling and functional imaging techniques offer alternative options to adrenal vein sampling (AVS) for unilateral and bilateral judgments in patients with PA. A combination of factors is needed to predict the prognosis of PA patients undergoing adrenalectomy in order to manage patient expectations of the outcome of the procedure and to closely monitor blood pressure and biochemical parameters in patients who suggest a poorer prognosis.
Sujet(s)
Surrénalectomie , Hyperaldostéronisme , Hyperaldostéronisme/chirurgie , Humains , Pronostic , Résultat thérapeutique , Aldostérone/sang , Aldostérone/métabolisme , Hypertension artérielle/chirurgie , Hypertension artérielle/étiologieRÉSUMÉ
Pseudohyperaldosteronism (PHA) is characterized by hypertension, hypokalemia, and a decrease in plasma renin and aldosterone levels. It can be caused by several causes, but the most frequent is due to excess intake of licorice. The effect is mediated by the active metabolite of licorice, glycyrrhetinic acid (GA), which acts by blocking the 11-hydroxysteroid dehydrogenase type 2 and binding to the mineralocorticoid receptor (MR) as an agonist. The management of licorice-induced PHA depends on several individual factors, such as age, gender, comorbidities, duration and amount of licorice intake, and metabolism. The clinical picture usually reverts upon licorice withdrawal, but sometimes mineralocorticoid-like effects can be critical and persist for several weeks, requiring treatment with MR blockers and potassium supplements. Through this case series of licorice-induced PHA, we aim to increase awareness about exogenous PHA, and the possible risk associated with excess intake of licorice. An accurate history is mandatory in patients with hypertension and hypokalemia to avoid unnecessary testing. GA is a component of several products, such as candies, breath fresheners, beverages, tobacco, cosmetics, and laxatives. In recent years, the mechanisms of action of licorice and its active compounds have been better elucidated, suggesting its benefits in several clinical settings. Nevertheless, licorice should still be consumed with caution, considering that licorice-induced PHA is still an underestimated condition, and its intake should be avoided in patients with increased risk of licorice toxicity due to concomitant comorbidities or interfering drugs.
Sujet(s)
Énoxolone , Glycyrrhiza , Hyperaldostéronisme , Humains , Glycyrrhiza/effets indésirables , Femelle , Mâle , Adulte d'âge moyen , Énoxolone/pharmacologie , Adulte , Hypokaliémie/induit chimiquement , 11-beta-Hydroxysteroid dehydrogenase type 2/métabolisme , Sujet âgé , Hypertension artérielle , Aldostérone/métabolisme , Aldostérone/sang , Rénine/sang , Rénine/métabolismeRÉSUMÉ
BACKGROUND: Evidence suggests that increasing salt intake in pregnancy lowers blood pressure, protecting against preeclampsia. We hypothesized that sodium (Na+) evokes beneficial placental signals that are disrupted in preeclampsia. METHODS: Blood and urine were collected from nonpregnant women of reproductive age (n=26) and pregnant women with (n=50) and without (n=55) preeclampsia, along with placental biopsies. Human trophoblast cell lines and primary human trophoblasts were cultured with varying Na+ concentrations. RESULTS: Women with preeclampsia had reduced placental and urinary Na+ concentrations, yet increased urinary angiotensinogen and reduced active renin, aldosterone concentrations, and osmotic response signal TonEBP (tonicity-responsive enhancer binding protein) expression. In trophoblast cell cultures, TonEBP was consistently increased upon augmented Na+ exposure. Mechanistically, inhibiting Na+/K+-ATPase or adding mannitol evoked the TonEBP response, whereas inhibition of cytoskeletal signaling abolished it. CONCLUSIONS: Enhanced Na+ availability induced osmotic gradient-dependent cytoskeletal signals in trophoblasts, resulting in proangiogenic responses. As placental salt availability is compromised in preeclampsia, adverse systemic responses are thus conceivable.
Sujet(s)
Placenta , Pré-éclampsie , Sodium , Trophoblastes , Humains , Femelle , Pré-éclampsie/métabolisme , Pré-éclampsie/physiopathologie , Grossesse , Trophoblastes/métabolisme , Trophoblastes/effets des médicaments et des substances chimiques , Adulte , Placenta/métabolisme , Placenta/effets des médicaments et des substances chimiques , Sodium/métabolisme , Sodium/urine , Aldostérone/métabolisme , Angiotensinogène/métabolisme , Cellules cultivées , Sodium-Potassium-Exchanging ATPase/métabolisme , Pression sanguine/physiologie , Pression sanguine/effets des médicaments et des substances chimiques , Rénine/métabolisme , Facteurs de transcriptionRÉSUMÉ
BACKGROUND: Somatic mutations have been observed to induce aldosterone-producing adenomas (APAs). These may be accelerated during pregnancy. Somatic PRKACA mutations are common in cortisol-producing adenomas (CPAs). However, their role in APAs, particularly aldosterone- and cortisol-producing adenomas (A/CPAs), is not well understood. This study aims to investigate the association between PRKACA mutations and the accelerated development of A/CPAs during pregnancy. CASE PRESENTATION: A patient with primary aldosteronism (PA) associated with severe Cushing's syndrome (CS) underwent surgical resection of an adrenal tumor one year after delivery. Pathologic examination revealed an adrenocortical adenoma characterized primarily by zona glomerulosa hyperplasia. Somatic mutation analysis revealed the presence of the somatic PRKACA mutation, which was validated as a deleterious mutation by various computational databases. Immunohistochemical results showed positive staining for cytochrome P450 family 11 subfamily B member 1 (CYP11B1), cytochrome P450 family 11 subfamily B member 2 (CYP11B2), and luteinizing hormone/chorionic gonadotropin receptor (LHCGR). Our study included a review of 20 previously documented cases of aldosterone- and cortisol-producing adenomas (A/CPAs), two of which were concurrently positive for both CYP11B1 and CYP11B2, consistent with our findings. CONCLUSION: Somatic mutations in PRKACA may correlate with the upregulation of LHCGR, which synergistically drives the accelerated growth of co-secretion tumors during pregnancy, thereby exacerbating disease progression.
Sujet(s)
Tumeurs corticosurrénaliennes , Adénome corticosurrénalien , Aldostérone , Cyclic AMP-Dependent Protein Kinase Catalytic Subunits , Hydrocortisone , Mutation , Complications tumorales de la grossesse , Humains , Femelle , Grossesse , Adulte , Hydrocortisone/métabolisme , Adénome corticosurrénalien/génétique , Adénome corticosurrénalien/anatomopathologie , Adénome corticosurrénalien/métabolisme , Adénome corticosurrénalien/chirurgie , Tumeurs corticosurrénaliennes/génétique , Tumeurs corticosurrénaliennes/anatomopathologie , Tumeurs corticosurrénaliennes/métabolisme , Aldostérone/métabolisme , Cyclic AMP-Dependent Protein Kinase Catalytic Subunits/génétique , Complications tumorales de la grossesse/génétique , Complications tumorales de la grossesse/anatomopathologie , Hyperaldostéronisme/génétique , Hyperaldostéronisme/anatomopathologie , Hyperaldostéronisme/chirurgie , Syndrome de Cushing/génétique , Syndrome de Cushing/anatomopathologie , Adénomes/génétique , Adénomes/anatomopathologie , Adénomes/métabolismeRÉSUMÉ
Invasion and adhesion of neutrophils into tissues and their concomitant secretion play an important role in the development of vascular pathologies, including abdominal aortic aneurysm (AAA). Chronic administration of angiotensin II is used to initiate AAA formation in mice. The role of aldosterone in this process is being studied. We conducted for the first time a complex comparative study of the effects of angiotensin II and aldosterone on the adhesion of human neutrophils to fibronectin and the concomitant secretion of proteins, free amino acids as well as reactive oxygen (ROS) and nitrogen (NO) species. Neither angiotensin II nor aldosterone affected the attachment of neutrophils to fibronectin and the concomitant production of ROS. We showed for the first time that aldosterone stimulated the release of amino acid hydroxylysine, a product of lysyl hydroxylase, the activity of which is positively correlated with cell invasiveness. Aldosterone also initiates the secretion of matrix metalloproteinase 9 (MMP-9) and cathepsin G, which may reorganize the extracellular matrix and stimulate the recruitment and adhesion of neutrophils to the aortic walls. Angiotensin II did not affect protein secretion. It may contribute to neutrophil-induced vascular injury by inhibiting the production of NO or by increasing the secretion of isoleucine. Our results suggest that it is aldosterone-induced neutrophil secretion that may play a significant role in neutrophil-induced vascular wall destruction in angiotensin II-induced AAA or other vascular complications.
Sujet(s)
Aldostérone , Angiotensine-II , Adhérence cellulaire , Granulocytes neutrophiles , Espèces réactives de l'oxygène , Humains , Angiotensine-II/métabolisme , Angiotensine-II/pharmacologie , Granulocytes neutrophiles/effets des médicaments et des substances chimiques , Granulocytes neutrophiles/immunologie , Granulocytes neutrophiles/métabolisme , Aldostérone/métabolisme , Adhérence cellulaire/effets des médicaments et des substances chimiques , Espèces réactives de l'oxygène/métabolisme , Matrix metalloproteinase 9/métabolisme , Fibronectines/métabolisme , Cellules cultivées , Cathepsine G/métabolisme , Acides aminés/métabolisme , Espèces réactives de l'azote/métabolisme , Anévrysme de l'aorte abdominale/métabolisme , Anévrysme de l'aorte abdominale/anatomopathologieRÉSUMÉ
Hypertension remains a leading cause of cardiovascular and kidney diseases. Failure to control blood pressure with ≥ 3 medications or control requiring ≥ 4 medications is classified as resistant hypertension (rHTN) and new therapies are needed to reduce the resulting increased risk of morbidity and mortality. Here, we report genetic evidence that relaxin family peptide receptor 2 (RXFP2) is associated with rHTN in men, but not in women. This study shows that adrenal gland gene expression of RXFP2 is increased in men with hypertension and the RXFP2 natural ligand, INSL3, increases adrenal steroidogenesis and corticosteroid secretion in human adrenal cells. To address the hypothesis that RXFP2 activation is an important mechanism in rHTN, we discovered and characterized small molecule and monoclonal antibody (mAb) blockers of RXFP2. The novel chemical entities and mAbs show potent, selective inhibition of RXFP2 and reduce aldosterone and cortisol synthesis and release. The RXFP2 mAbs have suitable rat pharmacokinetic profiles to evaluate the role of RXFP2 in the development and maintenance of rHTN. Overall, we identified RXFP2 activity as a potential new mechanism in rHTN and discovered RXFP2 antagonists for the future interrogation of RXFP2 in cardiovascular and renal diseases.
Sujet(s)
Hypertension artérielle , Récepteurs couplés aux protéines G , Récepteurs peptidiques , Humains , Mâle , Hypertension artérielle/traitement médicamenteux , Hypertension artérielle/génétique , Récepteurs couplés aux protéines G/antagonistes et inhibiteurs , Récepteurs couplés aux protéines G/génétique , Récepteurs couplés aux protéines G/métabolisme , Animaux , Récepteurs peptidiques/génétique , Récepteurs peptidiques/métabolisme , Récepteurs peptidiques/antagonistes et inhibiteurs , Rats , Femelle , Anticorps monoclonaux/pharmacologie , Anticorps monoclonaux/usage thérapeutique , Glandes surrénales/métabolisme , Glandes surrénales/effets des médicaments et des substances chimiques , Résistance aux substances/génétique , Antihypertenseurs/pharmacologie , Aldostérone/métabolismeRÉSUMÉ
Reactive astrocytes are important pathophysiologically and synthesize neurosteroids. We observed that LPS increased immunoreactive TLR4 and key steroidogenic enzymes in cortical astrocytes of rats and investigated whether corticosteroids are produced and mediate astrocytic TLR4-dependent innate immune responses. We found that LPS increased steroidogenic acute regulatory protein (StAR) and StAR-dependent aldosterone production in purified astrocytes. Both increases were blocked by the TLR4 antagonist TAK242. LPS also increased 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) and corticosterone production, and both were prevented by TAK242 and by siRNAs against 11ß-HSD1, StAR, or aldosterone synthase (CYP11B2). Knockdown of 11ß-HSD1, StAR, or CYP11B2 or blocking either mineralocorticoid receptors (MR) or glucocorticoid receptors (GR) prevented dephosphorylation of p-Ser9GSK-3ß, activation of NF-κB, and the GSK-3ß-dependent increases of C3, IL-1ß, and TNF-α caused by LPS. Exogenous aldosterone mimicked the MR- and GSK-3ß-dependent pro-inflammatory effects of LPS in astrocytes, but corticosterone did not. Supernatants from astrocytes treated with LPS reduced MAP2 and viability of cultured neurons except when astrocytic StAR or MR was inhibited. In adrenalectomized rats, intracerebroventricular injection of LPS increased astrocytic TLR4, StAR, CYP11B2, and 11ß-HSD1, NF-κB, C3 and IL-1ß, decreased astrocytic p-Ser9GSK-3ß in the cortex and was neurotoxic, except when spironolactone was co-injected, consistent with the in vitro results. LPS also activated NF-κB in some NeuN+ and CD11b+ cells in the cortex, and these effects were prevented by spironolactone. We conclude that intracrine aldosterone may be involved in the TLR4-dependent innate immune responses of astrocytes and can trigger paracrine effects by activating astrocytic MR/GSK-3ß/NF-κB signaling.
Sujet(s)
Astrocytes , Glycogen synthase kinase 3 beta , Immunité innée , Lipopolysaccharides , Récepteur de type Toll-4 , Animaux , Astrocytes/métabolisme , Astrocytes/effets des médicaments et des substances chimiques , Récepteur de type Toll-4/métabolisme , Immunité innée/effets des médicaments et des substances chimiques , Rats , Glycogen synthase kinase 3 beta/métabolisme , Lipopolysaccharides/pharmacologie , Hormones corticosurrénaliennes/pharmacologie , Rat Sprague-Dawley , Cellules cultivées , Récepteurs des minéralocorticoïdes/métabolisme , Aldostérone/métabolisme , Aldostérone/pharmacologie , Mâle , Facteur de transcription NF-kappa B/métabolisme , Glycogen Synthase Kinase 3/métabolisme , Corticostérone/pharmacologieRÉSUMÉ
Osteocrin (OSTN) is an endogenous protein sharing structural similarities with the natriuretic peptides [NPs; atrial (ANP), B-type (BNP) and C-type (CNP) NP], which are hormones known for their crucial role in maintaining pressure/volume homeostasis. Osteocrin competes with the NPs for binding to the receptor involved in their clearance (NPR-C). In the present study, having identified, for the first time, the major circulating form of OSTN in human and ovine plasma, we examined the integrated haemodynamic, endocrine and renal effects of vehicle-controlled incremental infusions of ovine proOSTN (83-133) and its metabolism in eight conscious normal sheep. Incremental i.v. doses of OSTN produced stepwise increases in circulating concentrations of the peptide, and its metabolic clearance rate was inversely proportional to the dose. Osteocrin increased plasma levels of ANP, BNP and CNP in a dose-dependent manner, together with concentrations of their intracellular second messenger, cGMP. Increases in plasma cGMP were associated with progressive reductions in arterial pressure and central venous pressure. Plasma cAMP, renin and aldosterone were unchanged. Despite significant increases in urinary cGMP levels, OSTN administration was not associated with natriuresis or diuresis in normal sheep. These results support OSTN as an endogenous ligand for NPR-C in regulating plasma concentrations of NPs and associated cGMP-mediated bioactivity. Collectively, our findings support a role for OSTN in maintaining cardiovascular homeostasis.
Sujet(s)
GMP cyclique , Hémodynamique , Rein , Animaux , Ovis , Rein/métabolisme , GMP cyclique/métabolisme , Hémodynamique/effets des médicaments et des substances chimiques , Hémodynamique/physiologie , Facteur atrial natriurétique/métabolisme , Facteur atrial natriurétique/sang , Femelle , Peptide natriurétique cérébral/métabolisme , Rénine/métabolisme , Rénine/sang , AMP cyclique/métabolisme , Peptide natriurétique de type C/métabolisme , Aldostérone/sang , Aldostérone/métabolisme , Pression sanguine/physiologie , Pression sanguine/effets des médicaments et des substances chimiques , Peptides natriurétiques/métabolisme , NatriurèseRÉSUMÉ
PURPOSE OF REVIEW: Maintenance of plasma K + concentration within a narrow range is critical to all cellular functions. The kidneys are the central organ for K + excretion, and robust renal excretory responses to dietary K + loads are essential for survival. Recent advances in the field have challenged the view that aldosterone is at the center of K + regulation. This review will examine recent findings and propose a new mechanism for regulating K + secretion. RECENT FINDINGS: Local aldosterone-independent response systems in the distal nephron are increasingly recognized as key components of the rapid response to an acute K + load, as well as playing an essential role in sustained responses to increased dietary K + . The master kinase mTOR, best known for its role in mediating the effects of growth factors and insulin on growth and cellular metabolism, is central to these aldosterone-independent responses. Recent studies have shown that mTOR, particularly in the context of the "type 2" complex (mTORC2), is regulated by K + in a cell-autonomous fashion. SUMMARY: New concepts related to cell-autonomous K + signaling and how it interfaces with aldosterone-dependent regulation are emerging. The underlying signaling pathways and effectors of regulated K + secretion, as well as implications for the aldosterone paradox and disease pathogenesis are discussed.
Sujet(s)
Aldostérone , Néphrons , Potassium , Transduction du signal , Sérine-thréonine kinases TOR , Aldostérone/métabolisme , Humains , Néphrons/métabolisme , Animaux , Sérine-thréonine kinases TOR/métabolisme , Potassium/métabolisme , Complexe-2 cible mécanistique de la rapamycine/métabolismeRÉSUMÉ
INTRODUCTION: Our objective was to investigate the association between the presence of placental anastomoses and intertwin differences in renin-angiotensin-aldosterone activation in monochorionic twins using amniotic fluid aldosterone (AF-ALD) levels. In addition, this study also examined the association between AF-ALD and the ALD levels in the umbilical cord blood (UCB-ALD) in monochorionic twins. MATERIAL AND METHODS: This prospective study included monochorionic diamniotic (MD) twin pregnancies that were not complicated by twin-to-twin transfusion syndrome (TTTS) at delivery. Amniotic fluid and umbilical cord vein blood samples were collected from each twin at delivery, and the ALD levels were measured subsequently. The MD twins were divided into two groups: those with placental anastomoses and those without anastomoses owing to fetoscopic laser surgery. The differences in the AF-ALD levels between the larger and smaller twins were analyzed. RESULTS: The AF-ALD levels showed a strong and significant positive correlation with UCB-ALD levels in 131 MD twins (r = 0.804, p < 0.001). Intertwin differences were examined in 41 and 28 pairs of MD twins with and without placental anastomoses, respectively. The AF-ALD levels in the smaller twins were significantly higher than those in the larger twins among the pairs of MD twins with placental anastomoses (p = 0.003); however, no statistically significant intertwin differences were observed among the twins without placental anastomoses (p > 0.05). CONCLUSIONS: The AF-ALD levels reflect the UCB-ALD levels in MD twins. The presence of placental anastomoses led to intertwin discordance in the ALD levels in MD twins even uncomplicated with TTTS. It was considered that monochorionic twins have this clinical background, and it leads to the development of TTTS.
Sujet(s)
Aldostérone , Liquide amniotique , Syndrome de transfusion foeto-foetale , Placenta , Grossesse gémellaire , Humains , Femelle , Syndrome de transfusion foeto-foetale/chirurgie , Syndrome de transfusion foeto-foetale/métabolisme , Grossesse , Études prospectives , Liquide amniotique/métabolisme , Placenta/métabolisme , Aldostérone/sang , Aldostérone/métabolisme , Adulte , Jumeaux monozygotes , Sang foetal/composition chimique , Sang foetal/métabolismeRÉSUMÉ
OBJECTIVE: To develop and validate a nomogram combining radiomics and pathology features to distinguish between aldosterone-producing adenomas (APAs) and nonfunctional adrenal adenomas (NF-AAs). METHODS: Consecutive patients diagnosed with adrenal adenomas via computed tomography (CT) or pathologic analysis between January 2011 and November 2022 were eligible for inclusion in this retrospective study. CT images and hematoxylin & eosin-stained slides were used for annotation and feature extraction. The selected radiomics and pathology features were used to develop a risk model using various machine learning models, and the area under the receiver operating characteristic curve (AUC) was determined to evaluate diagnostic performance. The predicted results from radiomics and pathology features were combined and visualized using a nomogram. RESULTS: A total of 211 patients (APAs, n = 59; NF-AAs, n = 152) were included in this study, with patients randomly divided into either the training set or the testing set at a ratio of 8:2. The ExtraTrees model yielded a sensitivity of 0.818, a specificity of 0.733, and an accuracy of 0.756 (AUC = 0.817; 95% confidence interval [CI]: 0.675-0.958) in the radiomics testing set and a sensitivity of 0.999, a specificity of 0.842, and an accuracy of 0.867 (AUC = 0.905, 95% CI: 0.792-1.000) in the pathology testing set. A nomogram combining radiomics and pathology features demonstrated a strong performance (AUC = 0.912; 95% CI: 0.807-1.000). CONCLUSION: A nomogram combining radiomics and pathology features demonstrated strong predictive accuracy and discrimination capability. This model may help clinicians to distinguish between APAs and NF-AAs.
Sujet(s)
Tumeurs de la surrénale , Aldostérone , Humains , Femelle , Adulte d'âge moyen , Mâle , Études rétrospectives , Adulte , Aldostérone/métabolisme , Aldostérone/sang , Diagnostic différentiel , Tumeurs de la surrénale/imagerie diagnostique , Tumeurs de la surrénale/métabolisme , Tumeurs de la surrénale/anatomopathologie , Sujet âgé , Tomodensitométrie , Adénome corticosurrénalien/imagerie diagnostique , Adénome corticosurrénalien/métabolisme , Adénome corticosurrénalien/anatomopathologie , Nomogrammes , Adénomes/imagerie diagnostique , Adénomes/anatomopathologie , Adénomes/métabolisme , Tumeurs corticosurrénaliennes/imagerie diagnostique , Tumeurs corticosurrénaliennes/métabolisme , Tumeurs corticosurrénaliennes/anatomopathologie , Sensibilité et spécificité , Imagerie multimodale/méthodesRÉSUMÉ
Macrophages play crucial roles in organ-specific functions and homeostasis. In the adrenal gland, macrophages closely associate with sinusoidal capillaries in the aldosterone-producing zona glomerulosa. We demonstrate that macrophages preserve capillary specialization and modulate aldosterone secretion. Using macrophage-specific deletion of VEGF-A, single-cell transcriptomics, and functional phenotyping, we found that the loss of VEGF-A depletes PLVAP+ fenestrated endothelial cells in the zona glomerulosa, leading to increased basement membrane collagen IV deposition and subendothelial fibrosis. This results in increased aldosterone secretion, called "haptosecretagogue" signaling. Human aldosterone-producing adenomas also show capillary rarefaction and basement membrane thickening. Mice with myeloid cell-specific VEGF-A deletion exhibit elevated serum aldosterone, hypokalemia, and hypertension, mimicking primary aldosteronism. These findings underscore macrophage-to-endothelial cell signaling as essential for endothelial cell specialization, adrenal gland function, and blood pressure regulation, with broader implications for other endocrine organs.
Sujet(s)
Glandes surrénales , Aldostérone , Pression sanguine , Cellules endothéliales , Macrophages , Animaux , Macrophages/métabolisme , Aldostérone/métabolisme , Cellules endothéliales/métabolisme , Souris , Humains , Glandes surrénales/métabolisme , Glandes surrénales/anatomopathologie , Facteur de croissance endothéliale vasculaire de type A/métabolisme , Zone glomérulée/métabolisme , Zone glomérulée/anatomopathologie , Mâle , Hyperaldostéronisme/métabolisme , Hyperaldostéronisme/anatomopathologie , Hyperaldostéronisme/génétique , Souris de lignée C57BLRÉSUMÉ
Primary aldosteronism is the most common cause of secondary hypertension, which is caused by increased aldosterone secretion in the adrenal cortex and contains many subtypes, among which familial hyperaldosteronism is relatively rare. Familial hyperaldosteronism can be divided into four subtypes based on its clinical manifestations and mutated genes: FH-I , FH-II , FH-III , and FH-IV . This article reports on three patients with FH-IV: a mother and her two sons. They were diagnosed with hypertension in other hospitals, and hypokalemia was found during hospitalization in our department. Diltiazem and terazosin were used for elution for 1 month. Renin and aldosterone levels in standing or supine positions improved, and the aldosterone-to-renin ratio was positive. Primary aldosteronism was diagnosed based on improved saline and captopril inhibition tests. As the three patients were blood-related immediate family members, gene screening was performed, diagnosing them with FH-IV . This article reports the clinical characteristics of the three cases in combination with related literature to improve the understanding of FH-IV .