Search Results (38)

Background/Objectives: The purpose of this study was to evaluate the efficacy and safety of oral eplerenone in patients with acute and chronic central serous chorioretinopathy (CSCR). Methods: In this prospective study, 43 patients with CSCR and subretinal fluid on optical coherence tomography (OCT) at baseline were divided either to oral eplerenone (n = 23) or observation (n = 20). All subjects underwent best-corrected visual acuity (BCVA) measurement, OCT, and fluorescein angiography (FA) at baseline. The changes in BCVA and subretinal resolution (SRF) were examined at 1, 6, and 12 months after the initiation of treatment. Potential adverse events were recorded. Results: At month 6, SRF resolution was observed in 78.3% and 45% of the patients in the eplerenone and control groups, respectively (p = 0.024). However, there was a recurrence of fluid in three patients in the eplerenone group and in four patients in the control group. Therefore, at month 12, 65.2% of the patients in the eplerenone group and 25% in the control group had SRF resolution (p = 0.008). There was a statistically significant improvement in BCVA at 6 months (p < 0.001) and 12 months (p < 0.001) in the eplerenone group, while in the control group, there was an improvement in BCVA at 6 months (p = 0.079) and 12 months (p = 0.259), which did not reach statistical significance. Regarding adverse events, no ocular nor systemic adverse events were reported during the follow-up period, apart from dry mouth in 7 out of 23 patients (30.4%) taking eplerenone. Conclusions: Oral eplerenone was found to be a safe and effective treatment alternative for the management of CSCR in both acute and chronic cases, providing SRF resolution in approximately 65% of patients with significant improvement in visual acuity at the 12^th month of follow-up. Full article

Residual congestion (RC) at discharge predicts adverse outcomes in heart failure with reduced ejection fraction (HFrEF). Its impact on the implementation of guideline-directed medical therapies (GDMT) remains unclear. N-terminal pro-B-type natriuretic peptide (NT-proBNP) trajectory during hospitalisation reflects RC and may be associated with GDMT implementation. The aim was to assess whether discharge NT-proBNP and a fall in NT-proBNP < 30% during hospitalisation (ΔNT-proBNP < 30%) predict GDMT underuse in acute HFrEF. In this prospective observational study, NT-proBNP was measured at hospital admission and 48–72 h before discharge. Provision of individual GDMT drug classes was assessed and GDMT underuse was defined as prescription of <3 key GDMT drug classes at discharge. 391 HFrEF patients (mean age, 69.9 ± 13.1years, 67.3% male) were included. ΔNT-proBNP < 30% was identified in 108 (27.6%). Higher discharge NT-proBNP was independently associated with lower likelihood of prescribing ACE-inhibitors, sacubitril/valsartan, eplerenone/spironolactone, or empagliflozin/dapagliflozin. ΔNT-proBNP < 30% was associated with 17% higher odds of GDMT underuse (95% confidence interval, 1.10–1.31, p < 0.001), regardless of clinical characteristics or in-hospital management. Patients with ΔNT-proBNP < 30% were discharged on lower doses of titratable GDMT medications. In-hospital NT-proBNP burden and trajectory, as markers of RC, are associated with GDMT underutilisation at discharge in acute HFrEF. Addressing RC may impact treatment quality in acute HFrEF. Full article

More than 30% of diabetic patients develop dermatopathies linked to inflammation and increased vascular permeability. Considering the role of the renin–angiotensin–aldosterone system (RAAS) in diabetic complications, this study examined whether aldosterone (ALDO) and the mineralocorticoid receptor (MR) contribute to diabetes-related skin microangiopathy. Vascular permeability was measured in normoglycemic rats and insulin-dependent (streptozotocin-induced) diabetic rats. The expression of MR, 11β-hydroxysteroid dehydrogenase type 2 (HSD11β2), vascular endothelial growth factor (VEGF), von Willebrand factor (vWF), and the tight junction protein ZO-1 was determined by PCR and immunohistochemistry. Diabetic rats received the MR antagonist eplerenone (EPL, 100 mg/kg) for 10 days. Additionally, the effects of ALDO and EPL on endothelial permeability were evaluated in human dermal microvascular endothelial cells (HMEC-1) using a Transwell system. Diabetic rats showed skin atrophy, collagen damage, elevated ALDO levels, reduced MR and HSD11β2 expression, and increased vascular permeability, along with upregulation of VEGF and vWF. EPL markedly reduced these abnormalities. In vitro, ALDO increased endothelial permeability under hyperglycemia, and EPL counteracted this effect. These findings indicate that activation of the ALDO/MR pathway promotes skin vascular permeability in diabetes through VEGF- and vWF-dependent mechanisms. MR blockade limits these changes, suggesting therapeutic potential in preventing diabetes-associated skin complications. Full article

Through the mineralocorticoid receptor, aldosterone controls extracellular volume and arterial blood pressure by stimulating Na⁺ absorption and K⁺ secretion in epithelial cells of the kidney, colon, and several glands. Hyperaldosteronism promotes fibrosis and inflammation in epithelial and non-epithelial tissues, thereby favoring loss of kidney and heart function. Mineralocorticoid receptor blockade therefore gains relevance especially in renal and cardiac disease. Kidney-derived Klotho is a powerful anti-aging protein with anti-fibrosis and anti-inflammatory effects providing cardio- and nephroprotection. We wondered whether Klotho expression and production is influenced by mineralocorticoid receptor agonists and antagonists. Using four renal cell lines, Madin-Darby canine kidney (MDCK), normal rat kidney, subtype 52E (NRK-52E), human kidney 2 (HK2) cells, and primary renal proximal tubule epithelial cells (RPTECs), and the four most frequently prescribed mineralocorticoid receptor blockers, spironolactone, eplerenone, finerenone, and esaxerenone, we assessed Klotho gene expression by qRT-PCR and Klotho protein by Western blotting. Aldosterone and eplerenone did not significantly affect Klotho expression in either cell line. Spironolactone enhanced Klotho expression in MDCK and NRK-52E cells and downregulated Klotho in HK2 cells and RPTECs. Novel non-steroidal mineralocorticoid receptor antagonist finerenone downregulated Klotho expression in MDCK, NRK-52E, and low-dose finerenone in HK2 cells. To conclude, common mineralocorticoid receptor antagonists are characterized by highly diverse effects on Klotho in four renal cell lines. Further studies are needed to define the role of mineralocorticoid receptor blockade for Klotho production. Full article

The glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) are ligand-activated transcription factors that regulate epidermal homeostasis, inflammation, and function. Prior studies using epidermal-specific conditional single and double knockout mice have shown their importance in skin physiology; however, clinically human disease is largely treated pharmacologically. Our objective was to examine how systemic MR/GR antagonism affects cutaneous gene expression and epidermal thickness in aged (18-month-old) C57BL/6J female mice. Mice were treated with selective GR (relacorilant), selective MR (eplerenone), or dual GR/MR (miricorilant) antagonists for 8 weeks. Quantitative RT-qPCR analysis of the skin showed that miricorilant significantly upregulated Sgk1, a GR/MR target. Miricorilant also increased the expression of keratinocyte differentiation markers and downregulated key inflammatory cytokines and Col3a1, a collagen subtype associated with tissue remodeling. Relacorilant suppressed Scnn1g, a subunit of the epithelial sodium channel. None of the antagonists significantly altered proliferation markers, epidermal thickness, or regulators of glucocorticoid activity. Our findings show that miricorilant downregulated inflammatory cytokines and increased differentiation marker expression without affecting epidermal thickness, suggesting its potential to treat inflammatory skin diseases. The results contrast with data from GR/MR knockout studies, highlighting the likely significance of receptor dynamics. Further studies of antagonist effects on receptor interactions with co-regulators appear warranted. Full article

Esaxerenone, which blocks aldosterone binding, is approved to treat hypertension but not heart failure. We aimed to understand esaxerenone’s efficacy in treating chronic heart failure. This crossover study compared esaxerenone with eplerenone, an approved treatment for heart failure, in 66 patients with chronic heart failure complicated by hypertension (12 months for each drug). The primary endpoint was brain natriuretic peptide. The secondary endpoints included blood pressure; hormones and enzymes that regulate electrolytes and stress response; and biomarkers of kidney function. Change in brain natriuretic peptide concentration was significantly lower for esaxerenone compared with eplerenone at 3, 6, and 12 months. Blood pressure (all time points), plasma aldosterone concentration (3 and 6 months), and urinary albumin-to-creatinine ratio (3 and 6 months) were significantly lower for esaxerenone compared with eplerenone. The results suggest that esaxerenone more strongly blocks aldosterone binding than does eplerenone. This effect, together with its strong antihypertensive effect and reduced urinary albumin-to-creatinine ratio, suggests that esaxerenone improves kidney function. The results of this small-scale, single-center study need to be expanded to a larger-scale investigation, but esaxerenone shows promise as a treatment for chronic heart failure with hypertension. Full article

Smoltification is stressful for salmonids, and cortisol is one of the central endocrine regulators for seawater adaptation. It has been established that cortisol plays both mineralocorticoid and glucocorticoid functions by MR and GR, respectively, since the aldosterone hormone is absent. Recently, investigations have proposed that the 11-deoxycorticosterone (DOC) mineralocorticoid precursor might support cortisol effects, but this mechanism remains unclear. Hence, we assessed the early effects of DOC on rainbow trout pre-smolts, the key smoltification stage, via metabolic and transcriptomic approaches. Thirty-six juveniles (~120 g) were treated for 3 h with DOC (1 mg/kg) and/or mineralocorticoid (eplerenone) or glucocorticoid (mifepristone) receptor antagonists (n = 6 for each group). DOC decreased plasma glucose and pyruvate and increased phosphate and liver glycogen. DOC also downregulated carbohydrate metabolism-related genes in the liver. Finally, gill RNA-seq analysis presented 1660 differentially expressed transcripts in DOC versus vehicle, 1022 for eplerenone + DOC versus DOC and 3324 for mifepristone + DOC versus DOC. The enrichment analysis mainly revealed the upregulation of ion transmembrane transport and carbohydrate metabolism and the downregulation of stress and innate immune responses. This suggests a significant role of DOC in liver carbohydrate metabolism and gill osmoregulation of pre-smolts through both receptors. Hence, this could contribute to improving animal welfare monitoring during smoltification by featuring novel and potential biomarkers. Full article

Introduction: Finerenone, a third-generation non-steroidal mineralocorticoid receptor antagonist (MRA), offers a targeted approach to managing cardiovascular outcomes, particularly in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). Unlike traditional MRAs such as spironolactone and eplerenone, which can cause off-target hormonal side effects and hyperkalemia, Finerenone selectively binds to mineralocorticoid receptors, reducing these risks. Recent randomized controlled trials have demonstrated Finerenone’s potential to improve cardiovascular outcomes, making it a promising alternative in the management of heart failure and other cardiovascular conditions associated with CKD and T2D. Methods: We conducted a scoping review using PRISMA guidelines. A search for “Finerenone” in the PubMed, Embase, and Cochrane Library databases included randomized controlled trials (RCTs), post hoc analyses, and relevant meta-analyses on cardiovascular outcomes. Data were synthesized narratively, assessing study quality through strengths and limitations. Discussion: Finerenone has shown significant benefits and a superior safety profile compared with traditional MRAs like spironolactone and eplerenone in managing CKD, T2D, and heart failure. It effectively reduces cardiovascular and renal events while minimizing risks such as hyperkalemia and hormonal side effects associated with steroidal MRAs. Future studies, including the REDEFINE-HF, FINALITY-HF, and CONFIRMATION-HF trials, will further explore Finerenone’s potential across diverse heart failure phenotypes, including its role in heart failure with mildly reduced and preserved ejection fractions, potentially establishing it as a cornerstone therapy in heart failure management. Conclusions: Finerenone represents a significant advancement in MRA therapy, offering enhanced safety and efficacy in managing cardiovascular outcomes in CKD and T2D patients. The current evidence supports its use as a promising alternative to traditional MRAs, particularly in patients intolerant to steroidal MRAs. Further trials are needed to fully establish its potential across diverse patient populations, including those with varying heart failure phenotypes. Full article

Mineralocorticoid receptor antagonists (MRAs) are one of the renin–angiotensin–aldosterone system inhibitors widely used in clinical practice. While spironolactone and eplerenone have a long-standing profile in clinical medicine, finerenone is a novel agent within the MRA class. It has a higher specificity for mineralocorticoid receptors, eliciting less pronounced adverse effects. Although approved for clinical use in patients with chronic kidney disease and heart failure, intensive non-clinical research aims to further elucidate its mechanism of action, including dose-related selectivity. Within the field, animal models remain the gold standard for non-clinical testing of drug pharmacological and toxicological properties. Their role, however, has been challenged by recent advances in in vitro models, mainly through sophisticated analytical tools and developments in data analysis. Currently, in vitro models are gaining momentum as possible platforms for advanced pharmacological and pathophysiological studies. This article focuses on past, current, and possibly future in vitro cell models research with clinically relevant MRAs. Full article

In aquaculture, stress can negatively affect fish growth. For years, the cortisol hormone has been thought to play both glucocorticoid and mineralocorticoid functions. Nevertheless, recent research has suggested that 11-deoxycorticosterone (DOC) released during stress could contribute to cortisol actions, though this process is still misunderstood. Here, we evaluated the DOC effects on physiological and early transcriptional responses by RNA-seq. Juvenile rainbow trout were treated with DOC and/or glucocorticoids (mifepristone) or mineralocorticoid (eplerenone) receptor antagonists. Subsequently, plasma was collected, and cDNA libraries were generated from the gills of vehicle (control), DOC, mifepristone, mifepristone with DOC, eplerenone, and eplerenone with DOC groups. Calcium and phosphate levels in plasma were changed. Results revealed 914 differentially expressed transcripts (DETs) induced by DOC compared with control, mainly associated with sodium ion transmembrane transport, gluconeogenesis, negative regulation of transmembrane transport, and activation of innate immune response. DOC versus eplerenone with DOC comparison displayed 444 DETs related to cell-cell junction organization, canonical glycolysis, positive regulation of immune response, and potassium ion transport. Conversely, no DETs were detected in DOC versus mifepristone with DOC comparison. These data suggest that DOC has a relevant role in gill stress response and ion transport, which is differentially regulated by mineralocorticoid receptors. Full article

Background: High aldosterone levels contribute to kidney disease progression, while spironolactone in combination with ACEi or ARBs can potentially reduce proteinuria and ameliorate kidney function deterioration. However, evidence on the impact of eplerenone in patients with glomerulonephritis is scarce. Methods: In this prospective observational study, we assessed the effects of eplerenone in patients with biopsy-proven glomerulonephritis who were already treated with ACEi or ARBs. Patients received either eplerenone (25 mg daily) on top of ACEi or ARBs or standard treatment alone. Proteinuria (24 h total protein excretion), kidney function, blood pressure and serum K⁺ levels were assessed at 3, 6 and 12 months after the initiation of treatment. Results: Sixty-six patients were included in the study. Eplerenone was administered in 30 patients, while 36 received only ACEi or ARB. Proteinuria decreased from 1768 to 1152 mg/24 h after 1 year of eplerenone treatment, while it remained stable in controls. Eplerenone showed significant impact on proteinuria in those with baseline proteinuria of >1000 mg/24 h. Patients who received eplerenone showed a reduction in systolic blood pressure, while eGFR and serum K⁺ levels remained stable. Conclusions: Addition of eplerenone has a beneficial effect on proteinuria in patients with glomerulonephritis and significant baseline proteinuria. Full article

Diabetic cardiovascular complications are associated with up to 50% mortality, and current therapies are not effective enough. Renin–angiotensin–aldosterone system inhibitors (RAASis) are the standard of care for diabetic patients with hypertension and albuminuria. Based on our previous studies reporting the renoprotective effects of low-dose RAASis, here, we hypothesized that low-dose RAASi treatment has cardioprotective and antifibrotic benefits in type 1 diabetes mellitus (T1DM). After five weeks of T1DM, adult male Wistar rats received low doses of ramipril, losartan, or eplerenone for two weeks. Heart rate, blood pressure, and pulse wave velocity (PWV) were recorded. Aortic intima–media thickness (IMT), collagen accumulation, and myocardial fibrosis were assessed. All RAASis reduced PWV elevation, prevented the progression of myocardial fibrosis, and normalized B-type natriuretic peptide, troponin I, and fibroblast growth factor 23 levels without affecting blood pressure. Interestingly, only eplerenone reversed the decline in Klotho levels and reduced IMT and fibrosis in the media of the aorta. Our comparative analysis suggests that mineralocorticoid receptor antagonists, particularly eplerenone, may offer superior efficacy in halting both the arterial and the myocardial injuries in T1DM compared to angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers. Full article

Angiotensin II, a major culprit in cardiovascular disease, activates mediators that are also involved in pathological cardiac remodeling. In this context, we aimed at investigating the effects of two of them: aldosterone (Ald) and transforming growth factor beta-1 (TGF-β1) in an in vivo model. Six-week-old male wild-type (WT) and TGF-β1-overexpressing transgenic (TGF-β1-TG) mice were infused with subhypertensive doses of Ald for 2 weeks and/or treated orally with eplerenone from postnatal day 21. Thehearts’ ventricles were examined by morphometry, immunoblotting to assess the intracellular signaling pathways and RT qPCR to determine hypertrophy and fibrosis marker genes. The TGF-β1-TG mice spontaneously developed cardiac hypertrophy and interstitial fibrosis and exhibited a higher baseline phosphorylation of p44/42 and p38 kinases, fibronectin and ANP mRNA expression. Ald induced a comparable increase in the ventricular-heart-weight-to-body-weight ratio and cardiomyocyte diameter in both strains, but a less pronounced increase in interstitial fibrosis in the transgenic compared to the WT mice (23.6% vs. 80.9%, p < 0.005). Ald increased the phosphorylation of p44/42 and p38 in the WT but not the TGF-β1-TG mice. While the eplerenone-enriched chow partially prevented Ald-induced cardiac hypertrophy in both genotypes and interstitial fibrosis in the WT controls, it completely protected against additional fibrosis in transgenic mice. Ald appears to induce cardiac hypertrophy independently of TGF-β1, while in the case of fibrosis, the downstream signaling pathways of these two factors probably converge. Full article

Kidney injury molecule-1 (KIM-1) is a biomarker of renal injury and a predictor of cardiovascular disease. Aldosterone, via activation of the mineralocorticoid receptor, is linked to cardiac and renal injury. However, the impact of mineralocorticoid receptor activation and blockade on KIM-1 is uncertain. We investigated whether renal KIM-1 is increased in a cardiorenal injury model induced by L-NAME/ANG II, and whether mineralocorticoid receptor blockade prevents the increase in KIM-1. Since statin use is associated with lower aldosterone, we also investigated whether administering eiSther a lipophilic statin (simvastatin) or a hydrophilic statin (pravastatin) prevents the increase in renal KIM-1. Female Wistar rats (8–10 week old), consuming a high salt diet (1.6% Na+), were randomized to the following conditions for 14 days: control; L-NAME (0.2 mg/mL in drinking water)/ANG II (225 ug/kg/day on days 12–14); L-NAME/ANG II + eplerenone (100 mg/kg/day p.o.); L-NAME/ANG II + pravastatin (20 mg/kg/day p.o.); L-NAME/ANG II + simvastatin (20 mg/kg/day p.o.). Groups treated with L-NAME/ANG II had significantly higher blood pressure, plasma and urine aldosterone, cardiac injury/stroke composite score, and renal KIM-1 than the control group. Both eplerenone and simvastatin reduced 24-h urinary KIM-1 (p = 0.0046, p = 0.031, respectively) and renal KIM-1 immunostaining (p = 0.004, p = 0.037, respectively). Eplerenone also reduced renal KIM-1 mRNA expression (p = 0.012) and cardiac injury/stroke composite score (p = 0.04). Pravastatin did not affect these damage markers. The 24-h urinary KIM-1, renal KIM-1 immunostaining, and renal KIM-1 mRNA expression correlated with cardiac injury/stroke composite score (p < 0.0001, Spearman ranked correlation = 0.69, 0.66, 0.59, respectively). In conclusion, L-NAME/ANG II increases renal KIM-1 and both eplerenone and simvastatin blunt this increase in renal KIM-1. Full article

In aquaculture, many stressors can negatively affect growth in teleosts. It is believed that cortisol performs glucocorticoid and mineralocorticoid functions because teleosts do not synthesize aldosterone. However, recent data suggest that 11-deoxycorticosterone (DOC) released during stress events may be relevant to modulate the compensatory response. To understand how DOC modifies the skeletal muscle molecular response, we carried out a transcriptomic analysis. Rainbow trout (Oncorhynchus mykiss) were intraperitoneally treated with physiological doses of DOC in individuals pretreated with mifepristone (glucocorticoid receptor antagonist) or eplerenone (mineralocorticoid receptor antagonist). RNA was extracted from the skeletal muscles, and cDNA libraries were constructed from vehicle, DOC, mifepristone, mifepristone plus DOC, eplerenone, and eplerenone plus DOC groups. The RNA-seq analysis revealed 131 differentially expressed transcripts (DETs) induced by DOC with respect to the vehicle group, mainly associated with muscle contraction, sarcomere organization, and cell adhesion. In addition, a DOC versus mifepristone plus DOC analysis revealed 122 DETs related to muscle contraction, sarcomere organization, and skeletal muscle cell differentiation. In a DOC versus eplerenone plus DOC analysis, 133 DETs were associated with autophagosome assembly, circadian regulation of gene expression, and regulation of transcription from RNA pol II promoter. These analyses indicate that DOC has a relevant function in the stress response of skeletal muscles, whose action is differentially modulated by GR and MR and is complementary to cortisol. Full article