Expression of hippocampal corticosteroid receptors,as well as corticotrophin-releasing hormone and vasopressin in the hypothalamic paraventricular nucleus,in fornix transected rats

BACKGROUND： The hippocampus regulates the hypothalamic-pituitary-adrenal axis through negative feedback. The hypothalamic paraventricular nucleus receives neuronal input from the hippocampus via the fomix, OBJECTIVE： To explore whether the negative feedback effect of the hippocampus on the hypothalamic-pituitary-adrenal axis is contributed to the inhibitory effect of mineralocorticoid receptor （MR） and glucocorticoid receptor （GR） in the hippocampus on the paraventricular nucleus via the fornix. DESIGN, TIME AND SETTING： Randomized, controlled, animal experiment. The study was performed at the Department of Histology and Embryology, China Medical University between September 2006 and September 2008. MATERIALS： Rabbit anti-rat anti-MR and rabbit anti-rat anti-GR antibodies were purchased from Santa Cruz Biotechnology, USA. Rabbit anti-rat anti-corticotrophin releasing hormone （CRH） and rabbit anti-rat anti-arginine vasopressin antibodies were purchased from Wuhan Boster. METHODS： A total of 90 male, Wistar rats were randomly divided into model and sham-surgery groups （n = 45）. Fornix transection was performed in the model group, while the sham-surgery group underwent surgery, but no fornix transection. MAIN OUTCOME MEASURES： Immunohistochemistry was used to examine MR and GR expression in the hippocampus, as well as CRH and anti-arginine vasopressin in the paraventricular nucleus. Western blot was used to measure alterations in MR, GR, and CRH protein expression following fomix transection. RESULTS： Compared with the sham-surgery group, there were no obvious changes in MR and GR expression in the hippocampus, or CRH and anti-arginine vasopressin expression in the paraventdcular nucleus within 4 days of fornix transection. However, after 7-10 days, significantly decreased MR and GR expression in the hippocampus, and increased CRH and anti-arginine vasopmssin expression in the paraventricular nucleus were observed （P 〈 0.05-0.01）. CONCLUSION： Negative feedback from the hippocampus on the hypothalamic-pituitary-adrenal axis might be mediated through the fornix, and the corticosterene actions mediated by hippocampal corticosteroid receptors indirectly modulated the hypothalamic-pituitary-adrenal axis.

GRK5 is an essential co-repressor of the cardiac mineralocorticoid receptor and is selectively induced by finerenone

BACKGROUND In the heart,aldosterone(Aldo)binds the mineralocorticoid receptor(MR)to exert damaging,adverse remodeling-promoting effects.We recently showed that G protein-coupled receptor-kinase(GRK)-5 blocks the cardiac MR by directly phosphorylating it,thereby repressing its transcriptional activity.MR antagonist(MRA)drugs block the cardiac MR reducing morbidity and mortality of advanced human heart failure.Non-steroidal MRAs,such as finerenone,may provide better cardio-protection against Aldo than classic,steroidal MRAs,like spironolactone and eplerenone.AIM To investigate potential differences between finerenone and eplerenone at engaging GRK5-dependent cardiac MR phosphorylation and subsequent blockade.METHODS We used H9c2 cardiomyocytes,which endogenously express the MR and GRK5.RESULTS GRK5 phosphorylates the MR in H9c2 cardiomyocytes in response to finerenone but not to eplerenone.Unlike eplerenone,finerenone alone potently and efficiently suppresses cardiac MR transcriptional activity,thus displaying inverse agonism.GRK5 is necessary for finerenone’s inverse agonism,since GRK5 genetic deletion renders finerenone incapable of blocking cardiac MR transcriptional activity.Eplerenone alone does not fully suppress cardiac MR basal activity regardless of GRK5 expression levels.Finally,GRK5 is necessary for the antiapoptotic,anti-oxidative,and anti-fibrotic effects of both finerenone and eplerenone against Aldo,as well as for the higher efficacy and potency of finerenone at blocking Aldo-induced apoptosis,oxidative stress,and fibrosis.CONCLUSION Finerenone,but not eplerenone,induces GRK5-dependent cardiac MR inhibition,which underlies,at least in part,its higher potency and efficacy,compared to eplerenone,as an MRA in the heart.GRK5 acts as a co-repressor of the cardiac MR and is essential for efficient MR antagonism in the myocardium.

Renin-angiotensin system blockers-SGLT2 inhibitorsmineralocorticoid receptor antagonists in diabetic kidney disease:A tale of the past two decades!

Several pharmacological agents to prevent the progression of diabetic kidney disease(DKD)have been tested in patients with type 2 diabetes mellitus(T2DM)in the past two decades.With the exception of renin-angiotensin system blockers that have shown a significant reduction in the progression of DKD in 2001,no other pharmacological agent tested in the past two decades have shown any clinically meaningful result.Recently,the sodium-glucose cotransporter-2 inhibitor(SGLT-2i),canagliflozin,has shown a significant reduction in the composite of hard renal and cardiovascular(CV)endpoints including progression of end-stage kidney disease in patients with DKD with T2DM at the top of reninangiotensin system blocker use.Another SGLT-2i,dapagliflozin,has also shown a significant reduction in the composite of renal and CV endpoints including death in patients with chronic kidney disease(CKD),regardless of T2DM status.Similar positive findings on renal outcomes were recently reported as a top-line result of the empagliflozin trial in patients with CKD regardless of T2DM.However,the full results of this trial have not yet been published.While the use of older steroidal mineralocorticoid receptor antagonists(MRAs)such as spironolactone in DKD is associated with a significant reduction in albuminuria outcomes,a novel non-steroidal MRA finerenone has additionally shown a significant reduction in the composite of hard renal and CV endpoints in patients with DKD and T2DM,with reasonably acceptable side effects.

Glucocorticoid and mineralocorticoid receptor expression in critical illness:A narrative review

The glucocorticoid receptor(GCR)and the mineralocorticoid receptor(MR)are members of the steroid receptor superfamily of hormone-dependent transcription factors.The receptors are structurally and functionally related.They are localized in the cytosol and translocate into the nucleus after ligand binding.GCRs and MRs can be co-expressed within the same cell,and it is believed that the balance in GCR and MR expression is crucial for homeostasis and plays a key role in normal adaptation.In critical illness,the hypothalamic-pituitary-adrenal axis is activated,and as a consequence,serum cortisol concentrations are high.However,a number of patients exhibit relatively low cortisol levels for the degree of illness severity.Glucocorticoid(GC)actions are facilitated by GCR,whose dysfunction leads to GC tissue resistance.The MR is unique in this family in that it binds to both aldosterone and cortisol.Endogenous GCs play a critical role in controlling inflammatory responses in critical illness.Intracellular GC concentrations can differ greatly from blood levels due to the action of the two 11β-hydroxysteroid dehydrogenase isozymes,type 1 and type 2.11β-hydroxysteroid dehydrogenases interconvert endogenous active cortisol and intrinsically inert cortisone.The degree of expression of the two isozymes has the potential to dramatically influence local GC availability within cells and tissues.In this review,we will explore the clinical studies that aimed to elucidate the role of MR and GCR expression in the inflammatory response seen in critical illness.

Advances in Medical Treatment of Primary Aldosteronism

Primary aldosteronism(PA)is the most common form of secondary hypertension,with its main manifestations including hypertension and hypokalemia.Early identification of PA is extremely important as PA patients can easily develop cardiovascular complications such as atrial fibrillation,stroke,and myocardial infarction.The past decade has witnessed the rapid advances in the genetics of PA,which has shed new light on PA treatment.While surgery is the first choice for unilateral diseases,bilateral lesions can be treated with mineralocorticoid receptor antagonists(MRAs).The next-generation non-steroidal MRAs are under investigations.New medications including calcium channel blockers,macrophage antibiotics,and aldosterone synthase inhibitors have provided a new perspective for the medical treatment of PA.

MicroRNA-155 mediates endogenous angiotensin II type 1 receptor regulation:implications for innovative type 2 diabetes mellitus management

Type 2 diabetes mellitus(T2DM)is a lifelong condition and a threat to human health.Thorough understanding of its pathogenesis is acutely needed in order to devise innovative,preventative,and potentially curative pharmacological interventions.MicroRNAs(miRNA),are small,non-coding,one-stranded RNA molecules,that can target and silence around 60%of all human genes through translational repression.MiR-155 is an ancient,evolutionarily well-conserved miRNA,with distinct expression profiles and multifunctionality,and a target repertoire of over 241 genes involved in numerous physiological and pathological processes including hematopoietic lineage differentiation,immunity,inflammation,viral infections,cancer,cardiovascular conditions,and particularly diabetes mellitus.MiR-155 Levels are progressively reduced in aging,obesity,sarcopenia,and T2DM.Thus,the loss of coordinated repression of multiple miR-155 targets acting as negative regulators,such as C/EBPβ,HDAC4,and SOCS1 impacts insulin signaling,deteriorating glucose homeostasis,and causing insulin resistance(IR).Moreover,deranged regulation of the renin angiotensin aldosterone system(RAAS)through loss of Angiotensin II Type 1 receptor downregulation,and negated repression of ETS-1,results in unopposed detrimental Angiotensin II effects,further promoting IR.Finally,loss of BACH1 and SOCS1 repression abolishes cytoprotective,anti-oxidant,anti-apoptotic,and anti-inflam matory cellular pathways,and promotesβ-cell loss.In contrast to RAAS inhibitor treatments that further decrease already reduced miR-155 Levels,strategies to increase an ailing miR-155 production in T2DM,e.g.,the use of metformin,mineralocorticoid receptor blockers(spironolactone,eplerenone,finerenone),and verapamil,alone or in various combinations,represent current treatment options.In the future,direct tissue delivery of miRNA analogs is likely.

Aortic Cell Apoptosis in Rat Primary Aldosteronism Model

This study aimed to determine whether aldosterone could induce vascular cell apoptosis in vivo.Thirty-two male rats were randomly divided into 4 groups:vehicle(control),aldosterone,aldosterone plus eplerenone or hydralazine.They were then implanted with an osmotic mini-pump that infused either aldosterone or the vehicle.Systolic blood pressure(SBP) was measured weekly by the tail-cuff method.After 8 weeks,plasma aldosterone concentration(PAC) and renin activity(PRA) were determined by radioimmunoassay.Aorti...

Comparison of Cardiac Structural Improvement in Patients with Primary Aldosteronism after Surgical Therapy and Drug Therapy: A Meta-Analysis

Background: At present, in clinical practice, patients with primary hyperaldosteronism (PA) are mainly treated by surgery or medical drugs (spironolactone/spironolactone, epridone, etc.). Some studies show that the left ventricular hypertrophy of patients can be significantly improved after treatment. However, at present, the relevant research is very limited, and there is still controversy on the improvement of cardiac structure and function between the two treatment methods. No reliable conclusions have been drawn. Objective: We conducted this meta-analysis to compare the improvement of cardiac structure of patients after surgical treatment and drug treatment, so as to clarify the efficacy of surgical treatment and drug treatment for PA patients. Methods: In order to examine the cardiac color ultrasound data of PA patients receiving surgical treatment and drug therapy (spironolactone, antisterone), randomized or observational studies were searched through Pubmed, Cochrane Library, and Embase. Meta-analysis was then carried out on the comprehensive and individual outcomes. The ROINBS-I scale is utilized to assess the offset risk of study inclusion. Outcomes: A total of nine studies involving 799 patients with PA into meta analysis, according to the results of the surgery in the treatment of patients with PA, left ventricular mass index (LVMI) changes in value (drop range) is significantly higher than drug therapy (Mean difference IV: —2.32, P In 6 studies, after surgical treatment of interventricular septal thickness (IVSD), changes in value (drop range) are also higher than drug therapy (Mean difference IV: —0.35, P In 2 studies, the surgical treatment of plasma aldosterone concentration (PAC) drop degree is superior to drug therapy (Mean difference IV: —12.63, P < 0.05), and blood pressure to improve the degree of surgery and drug treatment has no obvious difference. Conclusions: This meta-analysis result confirmed that after medical and surgical treatment of PA can obviously improve the patient’s blood pressure, and no difference between the two treatments. But for the heart structure improvement, including left ventricular hypertrophy and interventricular septum thickness, surgical treatment effect is significantly better than the medicine treatment, so the adrenalectomy can be used as unilateral PA optimal choice of treatment.

Huoxue Jiedu Huayu recipe(活血解毒化瘀方)alleviates contralateral renal fibrosis in unilateral ureteral obstruction rats by inhibiting the transformation of macrophages to myofibroblast

OBJECTIVE:To investigate the action and underlying mechanisms of Huoxue Jiedu Huayu recipe(活血解毒化瘀方,HJHR)against unilateral ureteral obstruction(UUO)-induced injury in the contralateral kidney.METHODS:Forty-eight male Sprague-Dawley rats weighing(200±10)g were used in this study and randomly assigned to 4 groups:a sham group,a UUO group,a UUO+eplerenone(EPL)group,and a UUO+HJHR group.The contralateral kidneys were harvested for further study 180 d after surgery.Histological analysis,immunohistochemistry and immunofluorescence were used to study the fibrosis of the contralateral kidneys obtained from UUO rats.Contralateral kidney damagerelated pathway proteins were detected by real-time polymerase chain reaction and Western blot analysis.RESULTS:HJHR significantly inhibited fibrosis of the contralateral kidney in UUO rats by attenuating the UUOinduced macrophage-to-myofibroblast transition(MMT)in the contralateral kidney.Moreover,HJHR attenuated fibrosis in the contralateral kidney of UUO rats by preventing MMT through the aldosterone/mineralocorticoid receptor/serum/glucocorticoid regulated kinase 1 pathway.CONCLUSIONS:Our findings suggest that HJHR may be a potential treatment for renal interstitial fibrosis of obstructive nephropathy.

Efficacy of suspended moxibustion stimulating Shenshu(BL23)and Guanyuan(CV4)on the amygdala-HPA axis in rats with kidney-Yang deficiency symptom pattern induced by hydrocortisone

OBJECTIVE:To investigated the effects of suspended moxibustion stimulating Shenshu(BL23)and Guanyuan(CV4)acupoints on the amygdala and HPA axis in our rat model and elucidated the possible molecular mechanisms of moxibustion on kidney-Yang deficiency symptom pattern(KYDS).METHODS:Sixty male Sprague Dawley rats were randomly divided into a control group(n=12)and an experimental group(n=48).Rats in the experimental group were given intramuscular injections of hydrocortisone to establish a KYDS model.The 48 rats successfully modeled were then randomly divided into a model group(model,n=12),a carbenoxolone intraperitoneal injection group(CBX,n=12),a moxibustion group(moxi,n=12),and a moxi+CBX group(n=12).In the moxi,the Shenshu(BL23)and Guanyuan(CV 4)acupoints were treated with moxibustion for 14 d.After treatment,measures were taken of serum levels of corticosterone(CORT),adrenocorticotropic hormone(ACTH),and corticotropinreleasing hormone(CRH).The expression of mineralocorticoid receptors(MRs),glucocorticoid receptors(GRs),11beta-hydroxysteroid dehydrogenase type 1(11β-HSD1),CRH,and ACTH in the rats’amygdala,hypothalamus,or pituitary(as appropriate)was detected.Data were analyzed using one-way analysis of variance.RESULTS:Compared with those of the control group,the serum levels of CRH,ACTH,and CORT;the mRNA and protein expressions of MR,GR,and 11β-HSD1 in the amygdala;the mRNA and protein expressions of 11β-HSD1 in the hypothalamus;the CRH mRNA expression in the amygdala and hypothalamus;and the ACTH mRNA expression in the pituitary of the rats in the model group were all significantly decreased(P<0.05 or 0.01).After treatment with moxibustion,all the aforementioned observation indices except for 11β-HSD1 m RNA expression were ameliorated compared with those in the model group(P<0.05 or 0.01).CONCLUSIONS:Suspended moxibustion can effectively improve the serum levels of ACTH,CRH,and CORT and can up-regulate the mRNA and protein expressions of MR,GR,11β-HSD1,CRH,and ACTH in the amygdala and hypothalamus of KYDS rats.This may be one of the molecular mechanisms with which moxibustion alleviates KYDS.

Mosaic theory revised:inflammation and salt play central roles in arterial hypertension

The mosaic theory of hypertension was advocated by Irvine Page~80 years ago and suggested that hypertension resulted from the close interactions of different causes.Increasing evidence indicates that hypertension and hypertensive end-organ damage are not only mediated by the proposed mechanisms that result in hemodynamic injury.Inflammation plays an important role in the pathophysiology and contributes to the deleterious consequences of arterial hypertension.Sodium intake is indispensable for normal body function but can be detrimental when it exceeds dietary requirements.Recent data show that sodium levels also modulate the function of monocytes/macrophages,dendritic cells,and different T-cell subsets.Some of these effects are mediated by changes in the microbiome and metabolome due to high-salt intake.The purpose of this review is to propose a revised and extended version of the mosaic theory by summarizing and integrating recent advances in salt,immunity,and hypertension research.Salt and inflammation are placed in the middle of the mosaic because both factors influence each of the remaining pieces.