OBJECTIVES: To clarify the causal relationship between the level of cytoplasmic unactivated mineralocorticoid receptor (MR) and the development of tubulointerstitial nephritis (TIN), and to evaluate the impact of MR on dyslipidemia, particularly secondary hyperlipemia, in patients with diabetic kidney disease. METHODS: We conducted a two-sample Mendelian randomization study using genome-wide association study (GWAS) summary data. Genetic variants associated with MR levels were selected as exposures, with TIN and lipid profiles [including low-density lipoprotein cholesterol (LDL-C), triglyceride, and high-density lipoprotein cholesterol] as outcomes. A two-step Mendelian randomization approach was used to assess TIN as a mediator, employing inverse variance weighted regression as the primary analysis, supplemented by Mendelian randomization-Egger, weighted median, and sensitivity analyses. RESULTS: Cytoplasmic unactivated MR level exhibited a significant causal association with a decreased risk of TIN (OR = 0.8598, 95% CI [0.7775-0.9508], P < 0.001). Although no significant causal relationship was identified between MR level and secondary hyperlipemia, a potential association of cytoplasmic unactivated MR level with lower LDL-C levels was observed (OR = 0.9901, 95% CI [0.9821-0.9983], P = 0.018). Additionally, TIN exhibited causal links with secondary hyperlipemia (OR = 1.0016, 95% CI [1.0002-1.0029], P = 0.020) and elevated LDL-C (OR = 1.0111, 95% CI [1.0024-1.0199], P = 0.012), particularly LDL-C in European males (OR = 1.0230, 95% CI [1.0103-1.0358], P < 0.001). Inverse Mendelian randomization analysis revealed causal relationships between TIN and genetically predicted triglyceride (OR = 0.7027, 95% CI [0.6189-0.7978], P < 0.001), high-density lipoprotein cholesterol (OR = 1.1247, 95% CI [1.0019-1.2626], P = 0.046), and LDL-C (OR = 0.8423, 95% CI [0.7220-0.9827], P = 0.029). Notably, TIN mediated 16.7% of the causal association between MR and LDL-C levels. CONCLUSIONS MR plays a critical role in the development of TIN and lipid metabolism, highlighting the potential of MR-antagonists in reducing renal damage and lipid metabolism-associated complications.
Humans ; Mendelian Randomization Analysis ; Nephritis, Interstitial/metabolism* ; Receptors, Mineralocorticoid/genetics* ; Lipid Metabolism/genetics* ; Genome-Wide Association Study ; Male ; Female ; Polymorphism, Single Nucleotide ; Dyslipidemias/metabolism*

OBJECTIVE: To observe the effect of wheat-grain moxibustion on behavior, 5-hydroxytryptamine (5-HT) and cortisol in the serum, mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) in the hippocampus in rats with hypothyroidism complicated with depression, and to explore the possible mechanism of wheat-grain moxibustion on improving depression in rats with hypothyroidism. METHODS: A total of 32 SPF SD rats were randomly divided into a blank group, a model group, a medication group and a wheat-grain moxibustion group, 8 rats in each group. Except for the blank group, the rats in the remaining groups were treated with intragastric administration of 0.1% propylthiouracil (PTU) suspension at 1 mL/100 g, once a day for 4 weeks to establish the rat model of hypothyroidism, and whether the rats were accompanied with depression-like behavior determined through behavioristics evaluation. The rats in the medication group were intervened with euthyrox at 0.9 mL/100 g, once a day, for 4 weeks; the rats in the wheat-grain moxibustion group were treated with wheat-grain moxibustion at "Dazhui" (GV 14), "Mingmen" (GV 4), "Shenshu" (BL 23) and "Pishu" (BL 20), 7 cones each acupoint, once a day, six times a week for 4 weeks. After the intervention, the depression status was observed by behavioristics test; the contents of thyroid stimulating hormone (TSH), total thyroxine (TT4), 5-HT and cortisol in the serum were detected by ELISA; the protein expressions of MR and GR in hippocampus were detected by Western blot; the expressions of MR mRNA and GR mRNA in the hippocampus were detected by real-time PCR. RESULTS: Before the intervention, compared with the blank group, the scores of open field test (OFT) were decreased and the immobility time of tail suspension test (TST) was prolonged (P<0.05); the serum TSH contents were increased and TT4 contents were decreased (P<0.01) in the other three groups. After the intervention, compared with the model group, the vertical score of OFT was increased and the immobility time of forced swimming test (FST) was prolonged in the medication group (P<0.05), while the scores of three items of OFT were increased (P<0.05, P<0.01), and the immobility time of FST and TST was shortened in the wheat-grain moxibustion group (P<0.01, P<0.05). Compared with the medication group, the immobility time of TST and FST in the wheat-grain moxibustion group was shorter (P<0.05, P<0.01). Compared with the blank group, in the model group, the contents of serum TSH and cortisol were increased (P<0.01, P<0.001), while the contents of serum TT4 and 5-HT were decreased (P<0.01, P<0.001). Compared with the model group, the contents of serum TT4 and 5-HT were increased, while the contents of serum TSH and cortisol were decreased in the medication group and wheat-grain moxibustion group (P<0.01, P<0.05). Compared with the blank group, the protein and mRNA expression of MR, GR in the hippocampus in the model group was decreased (P<0.01, P<0.05, P<0.001); compared with the model group, the protein and mRNA expression of MR in the hippocampus in the medication group were increased (P<0.05), and the protein expression of MR, GR and mRNA expression of MR in the hippocampus in the wheat-grain moxibustion group were increased (P<0.05, P<0.01). Compared with the medication group, the expression of MR mRNA in the wheat-grain moxibustion group was increased (P<0.05). CONCLUSION Wheat-grain moxibustion could significantly improve thyroid function and depression in rats with hypothyroidism. Its mechanism may be related to up-regulating the protein and mRNA expression of MR and GR in the hippocampus, and then affecting the expression of serum cortisol and 5-HT.
Acupuncture Points ; Animals ; Depression/therapy* ; Hippocampus/metabolism* ; Hydrocortisone/metabolism* ; Hypothyroidism/therapy* ; Moxibustion ; RNA, Messenger/metabolism* ; Rats ; Rats, Sprague-Dawley ; Receptors, Glucocorticoid/metabolism* ; Receptors, Mineralocorticoid/metabolism* ; Serotonin ; Thyrotropin/metabolism* ; Triticum/metabolism*

BACKGROUND: Striatin and caveolin-1 (cav-1) are scaffolding/regulating proteins that are associated with salt-sensitive high blood pressure and promote renal sodium and water reabsorption, respectively. The mineralocorticoid receptor (MR) interacts with striatin and cav-1, while aldosterone increases striatin and cav-1 levels. However, no in vivo data have been reported for the levels of these proteins in the kidney. METHODS: Male Wistar rats were intraperitoneally injected with normal saline solution, aldosterone alone (Aldo: 150 µg/kg body weight), or aldosterone after pretreatment with eplerenone, an MR blocker, 30 minutes before the aldosterone injection (eplerenone [Ep.]+Aldo). Thirty minutes after the aldosterone injection, the amount and localization of striatin and cav-1 were determined by Western blot analysis and immunohistochemistry, respectively. RESULTS: Aldosterone increased striatin levels by 150% (P<0.05), and cav-1 levels by 200% (P<0.001). Eplerenone had no significant effect on striatin levels, but partially blocked the aldosterone-induced increase in cav-1 levels. Aldosterone stimulated striatin and cav-1 immunoreactivity in both the cortex and medulla. Eplerenone reduced cav-1 immunostaining in both areas; however, striatin intensity was reduced in the cortex, but increased in the medulla. CONCLUSION: This is the first in vivo study demonstrating that aldosterone rapidly enhances renal levels of striatin and cav-1. Aldosterone increases striatin levels via an MR-independent pathway, whereas cav-1 is partially regulated through MR.
Aldosterone ; Animals ; Blotting, Western ; Caveolin 1 ; Humans ; Hypertension ; Immunohistochemistry ; Kidney ; Male ; Rats ; Rats, Wistar ; Receptors, Mineralocorticoid ; Sodium ; Sodium Chloride ; Water

BACKGROUND: There have been few studies to evaluate the prognostic implications of guideline-directed therapy according to the temporal course of heart failure. This study assessed the relationship between adherence to guideline-directed therapy at discharge and 60-day clinical outcomes in de novo acute heart failure (AHF) and acute decompensated chronic heart failure (ADCHF) separately. METHODS: Among 5,625 AHF patients who were recruited from a multicenter cohort registry of Korean Acute Heart Failure, 2,769 patients with reduced ejection fraction were analyzed. Guideline-directed therapies were defined as the use of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor II blocker (ARB), β-blocker, and mineralocorticoid receptor antagonist. RESULTS: In de novo AHF, ACEI or ARB reduced re-hospitalization (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.34–0.95), mortality (HR, 0.41; 95% CI, 0.24–0.69) and composite endpoint (HR, 0.52; 95% CI, 0.36–0.77) rates. Beta-blockers reduced re-hospitalization (HR, 0.62; 95% CI, 0.41–0.95) and composite endpoint (HR, 0.65; 95% CI, 0.47–0.90) rates. In ADCHF, adherence to ACEI or ARB was associated with only mortality and β-blockers with composite endpoint. CONCLUSION: The prognostic implications of adherence to guideline-directed therapy at discharge were more pronounced in de novo heart failure. We recommend that guideline-directed therapy be started as early as possible in the course of heart failure with reduced ejection fraction.
Angiotensins ; Cohort Studies ; Heart Failure ; Heart ; Humans ; Mortality ; Receptors, Mineralocorticoid

The renin-angiotensin system (RAS) is an important regulator of cirrhosis and portal hypertension. As hepatic fibrosis progresses, levels of the RAS components angiotensin (Ang) II, Ang-(1–7), angiotensin-converting enzyme (ACE), and Ang II type 1 receptor (AT1R) are increased. The primary effector Ang II regulates vasoconstriction, sodium homoeostasis, fibrosis, cell proliferation, and inflammation in various diseases, including liver cirrhosis, through the ACE/Ang II/AT1R axis in the classical RAS. The ACE2/Ang-(1–7)/Mas receptor and ACE2/Ang-(1–9)/AT2R axes make up the alternative RAS and promote vasodilation, antigrowth, proapoptotic, and anti-inflammatory effects; thus, countering the effects of the classical RAS axis to reduce hepatic fibrogenesis and portal hypertension. Patients with portal hypertension have been treated with RAS antagonists such as ACE inhibitors, Ang receptor blockers, and aldosterone antagonists, with very promising hemodynamic results. In this review, we examine the RAS, its roles in hepatic fibrosis and portal hypertension, and current therapeutic approaches based on the use of RAS antagonists in patients with portal hypertension.
Angiotensin-Converting Enzyme Inhibitors ; Angiotensins ; Cell Proliferation ; Fibrosis* ; Hemodynamics ; Humans ; Hypertension, Portal* ; Inflammation ; Liver Cirrhosis ; Mineralocorticoid Receptor Antagonists ; Receptors, Angiotensin ; Renin-Angiotensin System* ; Sodium ; Vasoconstriction ; Vasodilation

No abstract available.
Receptors, Mineralocorticoid*

Emerging evidence indicates that aldosterone and mineralocorticoid receptors (MRs) are associated with the pathogenesis of erectile dysfunction. However, the molecular mechanisms remain largely unknown. In this study, freshly isolated penile corpus cavernosum tissue from rats was treated with aldosterone, with or without MRs inhibitors. Nuclear factor (NF)-kappa B (NF-κB) activity was evaluated by real-time quantitative PCR, luciferase assay, and immunoblot. The results demonstrated that mRNA levels of the NF-κB target genes, including inhibitor of NF-κB alpha (IκB-α), NF-κB1, tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6), were higher after aldosterone treatment. Accordingly, phosphorylation of p65/RelA, IκB-α, and inhibitor of NF-κB kinase-β was markedly increased by aldosterone. Furthermore, knockdown of MRs prevented activation of the NF-κB canonical pathway by aldosterone. Consistent with this finding, ectopic overexpression of MRs enhanced the transcriptional activation of NF-κB by aldosterone. More importantly, the MRs antagonist, spironolactone blocked aldosterone-mediated activation of the canonical NF-κB pathway. In conclusion, aldosterone has an inflammatory effect in the corpus cavernosum penis, inducing NF-κB activation via an MRs-dependent pathway, which may be prevented by selective MRs antagonists. These data reveal the possible role of aldosterone in erectile dysfunction as well as its potential as a novel pharmacologic target for treatment.
Aldosterone/pharmacology* ; Animals ; Cytokines/biosynthesis* ; Gene Knockdown Techniques ; I-kappa B Kinase/antagonists & inhibitors* ; Interleukin-6/genetics* ; Male ; Mineralocorticoid Receptor Antagonists/pharmacology* ; NF-kappa B/genetics* ; Penis/metabolism* ; Protein Serine-Threonine Kinases/antagonists & inhibitors* ; RNA, Messenger/biosynthesis* ; Rats ; Rats, Inbred WKY ; Receptors, Mineralocorticoid/genetics* ; Signal Transduction/drug effects* ; Spironolactone/pharmacology* ; Transcriptional Activation ; Tumor Necrosis Factor-alpha/biosynthesis* ; NF-kappaB-Inducing Kinase

BACKGROUND/OBJECTIVES: Although Korean fermented foods contain large amounts of salt, which is known to exacerbate health problems, these foods still have beneficial effects such as anti-hypertension, anti-cancer, and anti-colitis properties. We hypothesized that ganjang may have different effects on blood pressure compared to same concentrations of salt. MATERIALS/METHODS: Sprague-Dawley rats were divided into control (CT), NaCl (NC), and ganjang (GJ) groups and orally administered with 8% NaCl concentration for 9 weeks. The systolic blood pressure (SBP), serum chemistry, Na⁺ and K⁺ concentrations and renal gene expressions were measured. RESULTS: The SBP was significantly increased in the NC group compared to the GJ and CT groups. In addition, the Na+ concentration in urine was higher in the GJ and NC groups than the CT group, but the urine volume was increased in the GJ group compared to the other groups. The serum renin levels were decreased in the GJ group compared to the CT group, while the serum aldosterone level was decreased in the GJ group relative to the NC group. The mRNA expression of the renin, angiotensin II type I receptor, and mineralocorticoid receptor were significantly lower in the GJ group compared to other groups. Furthermore, GJ group showed the lowest levels of genes for Na⁺ transporter in kidney cortex such as Na⁺/K⁺ ATPaseα1 (NKAα1), Na⁺/H⁺ exchanger 3 (NHE3), Na⁺/HCO₃⁻ co-exchanger (NBC), and carbonic anhydrases II (CAII). CONCLUSIONS: The decreased SBP in the GJ could be due to decreased renin and aldosterone levels in serum and increased urinary volume and excretion of Na⁺ with its transporter gene alteration. Therefore, ganjang may have antihypertensive effect despite its high contents of salt.
Aldosterone ; Angiotensin II ; Blood Pressure ; Carbonic Anhydrases ; Chemistry ; Gene Expression ; Hypertension ; Kidney Cortex ; Rats, Sprague-Dawley* ; Receptors, Mineralocorticoid ; Renin ; Renin-Angiotensin System ; RNA, Messenger

Resistant hypertension has for many decades been defined as difficult-to-treat hypertension in order to identify patients who may benefit from special diagnostic and/or therapeutic considerations. Recently, the term "refractory hypertension" has been proposed as a novel phenotype of antihypertensive failure, that is, patients whose blood pressure cannot be controlled with maximal treatment. Early studies of this phenotype indicate that it is uncommon, affecting less than 5% of patients with resistant hypertension. Risk factors for refractory hypertension include obesity, diabetes, chronic kidney disease, and especially, being of African origin. Patients with refractory are at high cardiovascular risk based on increased rates of known heart disease, prior stroke, and prior episodes of congestive heart failure. Mechanisms of refractory hypertension need exploration, but early studies suggest a possible role of heightened sympathetic tone as evidenced by increased office and ambulatory heart rates and higher urinary excretion of norepinephrine compared to patients with controlled resistant hypertension. Important negative findings argue against refractory hypertension being fluid dependent as is typical of resistant hypertension, including aldosterone levels, dietary sodium intake, and brain natriuretic peptide levels being similar or even less than patients with resistant hypertension and the failure to control blood pressure with use of intensive diuretic therapy, including both a long-acting thiazide diuretic and a mineralocorticoid receptor antagonist. Further studies, especially longitudinal assessments, are needed to better characterize this extreme phenotype in terms of risk factors and outcomes and hopefully to identify effective treatment strategies.
Aldosterone ; Blood Pressure ; Heart Diseases ; Heart Failure ; Heart Rate ; Humans ; Hypertension* ; Natriuretic Peptide, Brain ; Norepinephrine ; Obesity ; Phenotype ; Receptors, Mineralocorticoid ; Renal Insufficiency, Chronic ; Risk Factors ; Sodium, Dietary ; Spironolactone ; Stroke ; Sympathetic Nervous System ; Treatment Failure*

Hyponatremia and hyperkalemia in infancy can be attributed to various causes, originating from a variety of renal and genetic disorders. Pseudohypoaldosteronism type 1 (PHA1) is one of these disorders, causing mineralocorticoid resistance that results in urinary salt wasting, failure to thrive, metabolic acidosis, and dehydration. PHA1 is heterogeneous in etiology. Inactivating mutations in the NR3C2 gene (4q31.1), which encodes the mineralocorticoid receptor, causes a less severe autosomal dominant form that is restricted to the kidney, while mutations in the amiloride-sensitive epithelial sodium channel gene (alpha subunit=SCNN1A, 12p13; beta subunit=SCNN1b, 16p12.2-p12.1; gamma subunit=SCNN1G, 16p12) causes a more severe autosomal recessive form, which has systemic effects. Here we report a neonatal case of kidney restricted PHA1 (renal type of PHA1) who first showed laboratory abnormalities before obvious PHA1 manifestations, with two functional polymorphisms in the NR3C2 gene. This is the second genetically confirmed case in Korea and the first to show functional polymorphisms that have previously been reported in the literature.
Acidosis ; Dehydration ; Epithelial Sodium Channels ; Failure to Thrive ; Humans ; Hyperkalemia ; Hyponatremia ; Infant, Newborn* ; Kidney ; Korea ; Male* ; Pseudohypoaldosteronism* ; Receptors, Mineralocorticoid*