Mineralocorticoid Receptor Inhibitor Research Articles

#2549 Real world data of dapagliflozin effect on proteinuria in primary glomerulopathies in Croatia

Abstract Background and Aims SGLT2 inhibitors, namely dapagliflozin, proved to slow progression of kidney disease in randomized clinical trials. Our aim was to assess real world efficacy of dapagliflozin on proteinuria level in primary glomerulopathies (GN). Method adult patients with biopsy proven glomerulonephritis from all university hospitals in Croatia who started dapagliflozin as a standard of care were enrolled. Data were analyzed if patients had at least six months of follow up. None of the patients were on immunosuppression. Data are shown as N (%) or median with interquartile range (IQR) and accompanied p levels. Results Overall 118 patients, predominantly male 84 (71.8%) of average age of 52 years (min–max 20–76), were enrolled. Most of the patients had IgA nephropathy (IgAN) (N = 55;46.6%), followed by membranous nephropathy (N = 27;22.9%), FSGS (N = 19;16.1%), membranoproliferative GN (N = 8;6.8%), Alport syndrome (N = 8;6.8%). 95.8% of patients were on ACE inhibitors or angiotensin receptor blockers and 10.7% were on mineralocorticoid receptor inhibitors and RAAS blockage was not significantly upscaled during follow up. During the median follow up of 12.2 (7.5-18.6) months, proteinuria was significantly reduced from 1139 (534–2265) to 701 (305-1543) mg/dU; p < 0.001. When divided by glomerulonephritis type, statistically significant reduction of proteinuria was observed in patients with IgAN and Alport syndrome, while trend of reduction of proteinuria was observed in all types of GN. There was a slight reduction in eGFR levels (54 (43-78) vs. 52 (39–73) ml/min/1,73 m²; p < 0.001) and rise in creatinine values (122 (89–149) vs. 128 (91–159) μmol/l; p < 0.001). There was a significant reduction in systolic (130 (120-140) vs.125 (115-134) mmHg; p < 0.001) and diastolic blood pressure (80 (75-90) vs. 80 (70-85) mmHg; p < 0.001). Reduction of uric acid level was noticed (377 (313–460) vs.343 (294–422); p < 0.001), while there was no effect on LDL levels (2.6 (2.12–3.53) vs.2.3 (1.9–3.30); p = 0.073). Dapagliflozin was well tolerated, one patient discontinued the therapy due to intolerance, one due to urinary infection and two due to relapse of GN which needed immunosuppressive therapy. One patient was excluded from analysis due to non-adherence. Conclusion SGLT2 inhibitor dapagliflozin has significant effect on reduction of proteinuria in patients with primary glomerulonephritis. Our data support a growing body of evidence that SGLT2 inhibitors should be used as a standard of care in patients with glomerular kidney diseases, especially IgAN. Future research should address earlier use of SGLT2 inhibitors during the treatment of glomerulonephritis alongside immunosuppressive therapy as well as look into the effect of SGLT2 inhibitors on mesangial cells.

#1816 CA 125 as a surrogate marker for plasma volume in patients with cardiorenal syndrome

Abstract Background and Aims Assessing volume status in heart failure (HF) and end-stage chronic kidney disease (CKD) is challenging. Plasma volume expansion is an early step in the pathophysiology of decompensated HF and an independent risk factor for death and HF hospitalization, and should be addressed early. Evaluating plasma volume, especially its variation with diuretic therapy, can be a useful clinical tool for guiding decongestive therapy. There's a growing need for accurate and simple tools to guide clinician decisions on patient volume management. Cancer antigen 125 (CA125), a glycoprotein produced in mesothelial cells in the pericardium, pleura, or peritoneum, is primarily associated with ovarian and gynecological malignancies. Recent studies link CA125 to inflammation and congestion. In acute HF, elevated CA125 is associated with fluid overload indicators like increased central venous and pulmonary wedge pressure. Elevated CA125 in acute HF patients is linked to worse outcomes in death and hospital stay length. Evidence supports CA125-guided therapy in acute HF, but its role in managing chronic volume overload is still uncertain. We aim to assess the relationship between CA125 levels and estimated plasma volume (ePV). Method A retrospective unicentric observational study was conducted between June 2022, and April 17, 2023, at the Renocardiac clinic of a tertiary hospital. Clinical data were extracted from electronic patient records. CKD staging was determined following the Kidney Disease Improving Global Outcomes (KDIGO) classification. ePV was calculated using the Kaplan-Hakim formula. CA125 and ePV were assessed for the same patient in 2 different visits and their variation was calculated. The correlation between CA125 and ePV, as well as CA125 and ePV variation, was evaluated using Spearman's rank correlation coefficient for bivariate analysis, conducted with IBM SPSS®. Results This study comprised 65 patients, totaling 124 hospital visits. The patient demographic was 67.7% male, with a mean age of 76.4 (±12.47) years. In terms of CKD staging, 48.5% were classified as KDIGO 5, 40.6% as KDIGO 4, 9.4% as KDIGO 3, and 1.5% as KDIGO 2. HF etiology distribution included 59% ischemic, 9.8% hypertensive, 6.5% valvular, and 24.5% other causes. The mean ejection fraction was 37.35 (±12.36)% and 19% had preserved ejection fraction; 75% of them were treated with prognostic-modifying medication, including SGLT2 inhibitors. This proportion was lower (19%) in patients with reduced ejection fraction, receiving ACE/angiotensin ± neprilysin inhibitor + mineralocorticoid receptor inhibitor + beta-blocker + SGLT2 inhibitor. During the follow-up period, 13 hospitalizations, 1 major adverse cardiovascular event (MACE), and 5 deaths were recorded. The mean CA125 level was 193.98 (±154.55) U/mL, and patients had a mean ePV of 2.41 (±1.19) L. A significant positive correlation was found between CA125 levels and ePV (r = 0.355, p = 0.000). However, there was no significant correlation between the variation of CA125 and ePV levels between visits (p = 0.535). Conclusion This study focuses on a population with limited implementation of disease-modifying therapy due to advanced CKD, complicating the clinical management of volume status, kidney function, potassium levels, and long-term prognosis in both CKD and HF. CA125 shows potential clinical utility as a marker of congestion, aiding clinicians in assessing volume status by correlating with plasma volume. However, this study found no correlation between CA125 variation and changes in plasma volume. The outpatient nature of the studied population, typically euvolemic, may hinder assessing the relationship between CA125 and ePV changes. Future studies with larger sample sizes are essential to clarify this relationship and potentially identify volume-expanded patients early.

The impact of outpatient pharmacological optimization on echocardiographic parameters in heart failure with reduced ejection fraction

Abstract Background The 2022 landmark STRONG-HF study demonstrated that aggressive uptitration of guideline directed medical therapy (GDMT) in patients recently hospitalized for heart failure leads to a reduction in the composite endpoint of heart failure hospitalization and mortality. However, the impact of optimization of GDMT on echocardiographic parameters in heart failure with reduced ejection fraction (HFrEF) is unknown. Purpose This goal of this study was to determine the impact of a virtual HFrEF optimization program for achieving GDMT uptake and its impacts of echocardiographic parameters. Methods We conducted a single center study at a Canadian community cardiovascular centre using a prospective pre-post design. NYHA class II/III HFrEF patients referred from inpatient and outpatient settings were enrolled in our virtual 3-month HFrEF optimization program. All participants underwent an initial consult with a nurse and cardiologist. After this, all patients were seen remotely by a nurse every two weeks for adjustment of HFrEF medications with the goal of maximally tolerated GDMT dosing within 3 months was. Transthoracic echocardiograms were performed prior to participation in the program & after completion. Results Over 9 months, 284 NYHA class II/III HFrEF patients enrolled in the virtual HFrEF optimization program. Mean age was 67 and 70% were male. Mean ejection fraction was 34% and 54% had New York Heart Association Class II symptoms. At intake, the proportion of patients prescribed each class of GDMT was: 69% for Beta-blockers, 23% for Mineralocorticoid Receptor Inhibitors (MRA), 16% for Valsartan-Sacubitril and 7% for SGLT2 inhibitors. At 3-month follow-up, rates of GDMT prescription were improved: 90% for beta-blockers (p<0.01), 71% for MRA (p<0.01), 95% for ARNI (p<0.01) and 79% for SGLT2i (p<0.01). From baseline to follow-up echocardiogram, mean Left Ventricular End Diastolic Diameter improved from 5.51 to 5.13 cm (p<0.01). Mean Left Ventricular End Systolic Diameter improved from 4.33 to 3.75 cm (p<0.01). Mean Left Ventricular Mass Index was improved from 112.5 to 102.5 g/m2 (p<0.01). Mean Left Ventricular Ejection Fraction improved 34.4% to 49.8% (p<0.01). No hospitalizations due to medication-related adverse events were reported and 18 patients were hospitalized for HF exacerbation during study follow-up. Mean serum creatinine increased from 97.4 to 104.5 µmol/L (p<0.01); mean serum potassium increased from 4.48 to 4.58 (p<0.01). Conclusions This study demonstrates that a virtual program for GDMT optimization can safely and rapidly promote uptake of therapy in HFrEF patients. Furthermore, medical optimization was associated with significant reductions in left ventricular size, mass and ejection fraction. This provides a structural explanation for reductions in morbidity and mortality seen in STRONG-HF. Future studies should examine the effect of similar interventions on patient outcomes in a randomized setting.

Eplerenone for the Treatment of Chronic Recurrent Chorioretinopathy Centralis Serosa.

Chorioretinopathy centralis serosa (CCS) is a common disease that leads to the loss of retinal ion/fluid homeostasis due to decompensation of the retinal pigment epithelium, resulting in fluid accumulation with detachment of the neurosensory retina and/or retinal pigment epithelium. We investigated the effect of eplerenone, a mineralocorticoid receptor inhibitor, on chronic recurrent CCS (cr-CCS). A retrospective study with data analysis of 17 eyes (12 patients) between 2014 - 2021 with cr-CCS in whom other methods were not effective, not applicable, or not desired, was performed. Duration of CCS was at least 12 months with at least one recurrence. Each patient received 25 mg (1st week) and 50 mg (from the 2nd week) for at least 3 months. In each case, best-corrected visual acuity and central and peripheral retinal thickness were measured by spectral-domain optical coherence tomography. Side effects were rated by the patients as "none", "mild" (noticeable but not affecting), "tolerable" (affecting but acceptable because of good effect), and "not tolerable" (then discontinuation of therapy). There was no significant reduction in central or peripheral retinal thickness. A complete reduction of subretinal fluid was achieved in 5 of 17 eyes (29.4%). In 12 eyes, no effect of eplerenone could be detected, so other therapies were required. Visual acuity change was mainly dependent on the duration of CCS and the degree of photoreceptor damage. Side effects were reported by 11 patients as "none" and 1 patient as "mild" (arterial hypotension). No other side effects were observed. The response rates of therapy with eplerenone were relatively low, and no significant effect could be demonstrated. Eplerenone should not (no longer) be routinely used in the therapy of cr-CCS.

Decaying kidney function during cirrhosis correlates with remodeling of distal colon aldosterone target gene expression.

Liver cirrhosis is associated to circulatory abnormalities leading to hypovolemia and stimulation of the renin-angiotensin-aldosterone system (RAAS). Advanced stages of the disease cause renal failure, impairing K+ and Na+ homeostasis. It has been proposed that the distal colon undergoes functional remodeling during renal failure, in particular by aldosterone-driven increased K+ excretion. In this study, we compared the transcriptional response of aldosterone target genes in the rat distal colon under two models of increased circulating aldosterone (one with concomitant RAAS activation) and in a model of secondary hyperaldosteronism induced by cirrhosis. The expression of a subset of these genes was also tested in distal colon biopsies from control subjects or patients with cirrhosis with varying levels of disease progression and treated or not with mineralocorticoid receptor inhibitor spironolactone. We examined known aldosterone-regulated transcripts involved in corticosteroid signaling and transepithelial ion transport. In addition, we included aldosterone-regulated genes related to cell proliferation. Our comparison revealed multiple aldosterone target genes upregulated in the rat distal colon during decompensated cirrhosis. Epithelial Na+ channel β and γ subunit expression correlated positively with plasma aldosterone concentration and negatively with glomerular filtration rate. Patients with cirrhosis showed increased expression of 11-β-hydroxysteroid-dehydrogenase 2 (11βHSD2), which was reverted by spironolactone treatment, suggesting a sensitization of the distal colon to aldosterone action. In summary, our data show that decaying kidney function during cirrhosis progression toward a decompensated state with hypovolemia correlates with remodeling of distal colon ion transporter expression, supporting a role for aldosterone in the process.NEW & NOTEWORTHY Liver cirrhosis progression significantly alters ion transporter subunit expression in the rat distal colon, a change that correlated well with declining kidney function and the severity of the disease. Our data suggest that the steroid hormone aldosterone participates in this homeostatic response to maintain electrolyte balance.

The use of quadrotherapy of chronic heart failure in cancer patients (case series)

Background: Chronic heart failure (CHF) for a patient with cancer is complex, as it complicates antitumor treatment. In some cases, severe CHF is a contraindication to the chemotherapy or surgical treatment. Despite significant progress in CHF treatment, some groups of drugs, particularly mineralocorticoid receptor inhibitors, angiotensin receptor-neprilysin inhibitors, and sodium-glucose co-transporter type 2 inhibitors, have not been studied related to cancer patients. Clinical case description: In this report, we introduce two clinical cases in which, because of the invaluable contribution of the cardio-oncological team, we have managed to solve complex problems of treating patients with CHF and cancer. In patient 1 with severe CHF, it was possible to achieve regression of systolic dysfunction, despite the progression of bladder cancer T4N1M0. In patient 2 with severe ischemic cardiopathy and CHF, owing to the timely administration of quadruple therapy, we managed to significantly improve the cardiac status and increase the LV EF that the patient underwent gastrectomy and cholecystectomy for cancer of the cardiac part of the stomach cT2N0M0 without complications. Conclusion: The above clinical cases demonstrate the possibilities of a team, multidisciplinary approach in the treatment of complex category of patients with CHF and active oncological disease. Modern therapy of cancer patients with severe heart failure allows successful antitumor treatment.

The effects of different antihypertensive medications, steroids and beta blocker on COVID-19 outcomes in a biracial CKD and non-CKD cohort

Early on in the COVID-19 pandemic it was reported that angiotensin converting enzyme 2 inhibitors (ACE2i) could be associated with worse disease course due to potential increase in ACE2 receptors which SARS-CoV2 virus uses for cellular entry. Subsequent studies refuted such concerns, reporting that the continued use of ACEis and angiotensin receptor blockers (ARBs) in hypertensive individuals is in fact protective. Moreover, certain comorbidities, such as hypertension and heart disease, have been linked to an increased risk of disease severity. However, there is still paucity of data evaluating the effects of the use of different antihypertensive medications, steroids and beta blockers in chronic kidney disease (CKD) populations and in individuals with normal kidney function. This study was designed to evaluate the potential risk associated with renin angiotensin system inhibitors, calcium channel blocker, mineralocorticoid receptor blocker, steroids and beta blockers in a cohort of mostly African Americans and Caucasians. We conducted a retrospective study on patients who were admitted to the Detroit Medical Center, Detroit, MI during March and April of 2020. The data were collected through the medical chart reviews. We assessed 330 patients using inclusion criteria of age > 18 years and a positive SARS-CoV2 PCR test. We used the mean, standard deviation/standard error of mean, and percentages when appropriate for the description of patient characteristics. Group differences (CKD vs. non-CKD) were compared using the Pearson χ2 test. P-values of <0.05 were regarded as significant. We conducted binary logistic regression analysis to determine the effect of biological sex and CKD status on death due to COVID-19 during hospitalization. We conducted multivariate regression analysis for factors contributing to death during hospitalization due to COVID-19 and ICU admission, evaluating the contribution of different medications, comorbidities, and clinical course of the disease. On regression analyses, the odds of death in the hospital due to COVID-19 infection was not significantly associated with either biological sex or CKD status in our sample population. The odds of dying in the hospital were higher in patients who were on calcium channel blockers (OR 2.99, 95% CI 1.29-6.93, P = 0.01) and steroids (OR 4.23, 95% CI 1.17-15.31, P = 0.03). The only significance for ICU admission was obtained for steroid use (OR 1.872, 95% CI 1.059-3.311, P = 0.03). Likewise, COPD was the only comorbidity found to be associated with ICU admission (OR 2.38, 95% CI 1.282 - 4.426, P = 0.006), Significant associations were not observed for patients taking ACEis, ARBs, mineralocorticoid receptor inhibitors, diuretics, beta blockers and sympatholytics. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Profibrotic Effects of Endothelin-1 on Fibroblasts Are Mediated by Aldosterone in Vitro: Relevance to the Pathogenesis and Therapy of Systemic Sclerosis and Pulmonary Arterial Hypertension.

Endothelin-1 (ET-1) is a vasoactive and profibrotic peptide that plays a pivotal role in diseases such as systemic sclerosis (SSc) and pulmonary arterial hypertension (PAH), by inducing fibrosis and vascular remodeling. Such effects may be sustained by the induction of aldosterone production and reactive oxygen species (ROS). We have used fibroblasts obtained from skin of healthy donors and SSc patients and commercial fibroblasts from lung to evaluate whether ET-1 is able to stimulate ROS production directly or indirectly through aldosterone induction. We found that ET-1 receptors are present in all types of fibroblasts analyzed, whereas the expression of mineralocorticoid receptor (MCR) is lower in dermal fibroblasts from healthy donors (HDFs) compared to fibroblasts derived from lung (HPFs) or from skin of SSc patients (SScHDFs). ET-1 induces ROS production in HDFs and SScHDFs after 24 h of incubation involving its receptor B (ETB), whereas aldosterone exerts its effects after 40 min of incubation. Moreover, ROS production was inhibited by the pre-incubation of cells with MCR inhibitor. Our results indicate that ET-1 induces ROS indirectly through aldosterone production suggesting that aldosterone may play a pivotal role in the pathogenesis of SSc and PAH.

Current options for slowing the progression of chronic kidney disease.

From a certain stage, chronic kidney disease progresses to terminal kidney failure that requires renal replacement therapy with dialysis or transplantation. The progression can be significantly slowed by blocking the renin angiotensin aldosterone system (RAAS) with angiotensin converting enzyme (ACE) inhibitors or angiotensin II type 1 receptor blockers (ARB). Another new option to enhance the effect of blocking the RAAS system is the use of sodium glucose cotransporter 2 (SGLT2) inhibitors, or gliflozins. Dapagliflozin is currently available and reimbursed for patients with both diabetic and non-diabetic kidney disease. In the near future, treatment with the mineralocorticoid receptor inhibitor finerenone should be made available that significantly potentiates the effect of ACE or ARB inhibitors. Recent data show that it is possible to influence the progression of renal insufficiency with exercise.

Thiazides and mineralocorticoid receptor antagonists in chronic kidney disease

The latest treatment guidelines for patients with arterial hypertension continues to indicate as the first line therapy a minimal association between renin-angiotensin system (RAS) blockers and a thiazide-type or a thiazide-like diuretic. In addition, according to 2018 ESC/ESH (European Society of Cardiology/European Society of Hypertension) guidelines for the management of arterial hypertension, a mineralocorticoid receptor antagonist may be added in resistant hypertension cases (uncontrolled hypertension under at least 3 classes of antihypertensive drugs including a RAS blocker, thiazide diuretic and a calcium channel blocker) for general population. For chronic kidney disease (CKD) patients, achieving the optimal blood pressure (BP) level can be difficult because high complication rates can be encountered in any antihypertensive class mentioned, especially for RAS blockers and mineralocorticoid receptor inhibitors. This brief review aims to highlight the importance of diuretics use in CKD patients and the boundaries of their usage.

Nowe wytyczne leczenia niewydolności serca 2021

At this year’s ESC congress in London, it was announced an update of the guidelines for the treatment of chronic heart failure with reduced left ventricular ejection fraction. Key change compared to last guidelines is withdrawal the long-term titration strategy and introducing a simpler and faster regimen based on four groups of drugs: blocking the renin–angiotensin–aldosterone system (ACE-I, ARNI), sodium-glucose co-transporter inhibitors (dapagliflozin, empagliflozin), β-adrenolytic drugs, mineralocorticoid receptor inhibitors.

COVID-19 and renin angiotensin aldosterone system: Pathogenesis and therapy.

AimsThe severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) binds to the ACE2 component of the renin‐angiotensin aldosterone system (RAAS) and infects the human cells. The aims of the present review were to look at the role and alteration of the RAAS components in SARS‐CoV‐2 infection, therapeutic approaches, and clinical trials in this field.MethodsWe surveyed the literature (PubMed, Web of Science, and Scopus) till August 18, 2021, and 59 published papers regarding the components of the RAAS and their role and alterations in SARS‐CoV‐2 infection along with various COVID‐19 therapies based on the RASS components were included in the study.ResultsACE inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor inhibitors are agents that significantly enhance the ACE2 and Ang‐(1‐7) levels, which can be suggestive for their role as therapeutics against SARS‐CoV‐2 infection. Beta‐adrenergic blockers, which negatively regulate renin release from juxtaglomerular cells, and vitamin D, as a regulator of the RAAS and renin expression, are proposed therapeutics in the treatment of COVID‐19. Some antihyperglycemic agents could be potentially protective against COVID‐19‐induced lung injury. Also, the inhibition of the Janus kinase/signal transducer and activator of the transcription pathway as a potential treatment for COVID‐19 has been suggested. Finally, resveratrol, an antioxidant that can suppress Ang II, has been suggested as an adjunct to other therapies.ConclusionRegarding the suggested potential therapies for COVID‐19, there are many clinical trials whose results might change the treatment strategies of SARS‐CoV‐2 infection. So, the results of well‐organized clinical trials on the efficacy and safety of the mentioned agents in the treatment of COVID‐19 will be useful in the management and therapy of the disease.

Vascular cell-specific roles of mineralocorticoid receptors in pulmonary hypertension.

Abnormalities that characterize pulmonary arterial hypertension include impairment in the structure and function of pulmonary vascular endothelial and smooth muscle cells. Aldosterone levels are elevated in human pulmonary arterial hypertension and in experimental pulmonary hypertension, while inhibition of the aldosterone-binding mineralocorticoid receptor attenuates pulmonary hypertension in multiple animal models. We explored the role of mineralocorticoid receptor in endothelial and smooth muscle cells in using cell-specific mineralocorticoid receptor knockout mice exposed to sugen/hypoxia-induced pulmonary hypertension. Treatment with the mineralocorticoid receptor inhibitor spironolactone significantly reduced right ventricular systolic pressure. However, this is not reproduced by selective mineralocorticoid receptor deletion in smooth muscle cells or endothelial cells. Similarly, spironolactone attenuated the increase in right ventricular cardiomyocyte area independent of vascular mineralocorticoid receptor with no effect on right ventricular weight or interstitial fibrosis. Right ventricular perivascular fibrosis was significantly decreased by spironolactone and this was reproduced by specific deletion of mineralocorticoid receptor from endothelial cells. Endothelial cell-mineralocorticoid receptor deletion attenuated the sugen/hypoxia-induced increase in the leukocyte-adhesion molecule, E-selectin, and collagen IIIA1 in the right ventricle. Spironolactone also significantly reduced pulmonary arteriolar muscularization, independent of endothelial cell-mineralocorticoid receptor or smooth muscle cell-mineralocorticoid receptor. Finally, the degree of pulmonary perivascular inflammation was attenuated by mineralocorticoid receptor antagonism and was fully reproduced by smooth muscle cell-specific mineralocorticoid receptor deletion. These studies demonstrate that in the sugen/hypoxia pulmonary hypertension model, systemic-mineralocorticoid receptor blockade significantly attenuates the disease and that mineralocorticoid receptor has cell-specific effects, with endothelial cell-mineralocorticoid receptor contributing to right ventricular perivascular fibrosis and smooth muscle cell-mineralocorticoid receptor participating in pulmonary vascular inflammation. As mineralocorticoid receptor antagonists are being investigated to treat pulmonary arterial hypertension, these findings support novel mechanisms and potential mineralocorticoid receptor targets that mediate therapeutic benefits in patients.

Cardiovascular events as a № 1 killer. Pharmacotherapy of coronary heart disease

Cardiovascular events as a № 1 killer. Pharmacotherapy of coronary heart disease

Aldosterone enhances high phosphate-induced vascular calcification through inhibition of AMPK-mediated autophagy.

It remains unclear whether the necessity of calcified mellitus induced by high inorganic phosphate (Pi) is required and the roles of autophagy plays in aldosterone (Aldo)‐enhanced vascular calcification (VC) and vascular smooth muscle cell (VSMC) osteogenic differentiation. In the present study, we found that Aldo enhanced VC both in vivo and in vitro only in the presence of high Pi, alongside with increased expression of VSMC osteogenic proteins (BMP2, Runx2 and OCN) and decreased expression of VSMC contractile proteins (α‐SMA, SM22α and smoothelin). However, these effects were blocked by mineralocorticoid receptor inhibitor, spironolactone. In addition, the stimulatory effects of Aldo on VSMC calcification were further accelerated by the autophagy inhibitor, 3‐MA, and were counteracted by the autophagy inducer, rapamycin. Moreover, inhibiting adenosine monophosphate‐activated protein kinase (AMPK) by Compound C attenuated Aldo/MR‐enhanced VC. These results suggested that Aldo facilitates high Pi‐induced VSMC osteogenic phenotypic switch and calcification through MR‐mediated signalling pathways that involve AMPK‐dependent autophagy, which provided new insights into Aldo excess‐associated VC in various settings.

Aldosterone up-regulates voltage-gated potassium currents and NKCC1 protein membrane fractions

Na+–K+–2Cl− Cotransporter (NKCC1) is a protein that aids in the active transport of sodium, potassium, and chloride ions across cell membranes. It has been shown that long-term systemic treatment with aldosterone (ALD) can enhance NKCC1 protein expression and activity in the aging cochlea resulting in improved hearing. In the present work, we used a cell line with confirmed NKCC1 expression to demonstrate that in vitro application of ALD increased outward voltage-gated potassium currents significantly, and simultaneously upregulated whole lysate and membrane portion NKCC1 protein expression. These ALD-induced changes were blocked by applying the mineralocorticoid receptor antagonist eplerenone. However, application of the NKCC1 inhibitor bumetanide or the potassium channel antagonist Tetraethyl ammonium had no effect. In addition, NKKC1 mRNA levels remained stable, indicating that ALD modulates NKCC1 protein expression via the activation of mineralocorticoid receptors and post-transcriptional modifications. Further, in vitro electrophysiology experiments, with ALD in the presence of NKCC1, K+ channel and mineralocorticoid receptor inhibitors, revealed interactions between NKCC1 and outward K+ channels, mediated by a mineralocorticoid receptor-ALD complex. These results provide evidence of the therapeutic potential of ALD for the prevention/treatment of inner ear disorders such as age-related hearing loss.

Effect of Aldosterone on Senescence and Proliferation Inhibition of Endothelial Progenitor Cells Induced by Sirtuin 1 (SIRT1) in Pulmonary Arterial Hypertension.

BackgroundPulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary circulatory resistance. Pulmonary vascular endothelial dysfunction is one of the main causes of primary PAH. Endothelial progenitor cells (EPCs) can proliferate and differentiate into vascular endothelial cells and play an important role in maintaining normal endothelial function. Mineralocorticoid receptor inhibitor has been reported to be used in the treatment of PAH. However, the role and the underlying mechanism of aldosterone (ALDO) in PAH remains unclear.Material/MethodsRats were divided to 4 groups (n=10 per group) and treated with 0.9% normal saline, monocrotaline (MCT), spironolactone (SP), or MCT combined with SP. After the rats were sacrificed with an overdose of pentobarbital sodium, hematoxylin and eosin staining was performed to observe the pulmonary artery pathology section. Sirtuin 1 (SIRT1), p53, and p21 protein expression was detect by western blot. Immunofluorescence staining was performed to verify EPCs. EPCs were treated with different concentrations of ALDO. MTT assay and senescence-associated β-galactosidase staining were used to measure cell viability and senescence.ResultsMCT increased the vascular arterial wall thickness and wall area, inhibited SIRT1 protein expression and increased p53 and p21 protein expression in the lung tissue of rats, while SP partially reversed this effect. In addition, ALDO inhibited EPCs viability and induced senescence. The expression of p53 and p21 proteins in the EPCs were upregulated and the senescence was accelerated when EPCs were transfected with SIRT1 siRNA.ConclusionsALDO promoted EPCs senescence and inhibited EPCs proliferation by downregulating SIRT1, which regulates the p53/p21 pathway, thus promoting PAH.

Risk of hyperkalemia in heart failure patients and new treatment approaches

Introduction Hyperkalemia is a serious medical condition that can cause muscle weakness, paralysis and cardiac arrhythmias. In heart failure (HF), hyperkalemia is a frequent problem, because of several factors, such as chronic kidney disease (CKD), and because of medications, used to treat HF - angiotensin-converting enzyme inhibitors (ACEi)/Angiotensin II receptor blockers (ARBs) and mineralocorticoid receptor inhibitors (MRIs) that increase the serum potassium level, leading to a risk of hyperkalemia. Materials and Methods This is a retrospective study. The risk factors, leading to hyperkalemia among 535 patients, hospitalized for HF at the St. Marina University Hospital in Varna in the period January 2010 - December 2014 were analyzed. Results Significant part of the patients with HF have CKD as a comorbidity (56.3%), but they are treated with ACEi/ARBs (70.8%) and MRIs (34.2%), taking medications that increase the serum potassium level, leading to a risk of hyperkalemia. There are also a few patients per year (2.2%) who have hyperkalemia as a comorbidity, but they also must be treated with the same medications- ACEi/ARBs (91.7%) and MRIs (8.3%). Conclusion Two new potassium binders - patiromer and sodium zirconium cyclosilicate, are included in the current guidelines (2016) as medications under consideration for regulatory approval. They are new therapeutic options for managing hyperkalemia in patients with HF and a risk of hyperkalemia. The current study reveals the importance of minimizing this adverse effect in order to provide optimal pharmacological treatment for patients with HF.

Aldosterone induces albuminuria via matrix metalloproteinase–dependent damage of the endothelial glycocalyx

Aldosterone contributes to end-organ damage in heart failure and chronic kidney disease. Mineralocorticoid-receptor inhibitors limit activation of the receptor by aldosterone and slow disease progression, but side effects, including hyperkalemia, limit their clinical use. Damage to the endothelial glycocalyx (a luminal biopolymer layer) has been implicated in the pathogenesis of endothelial dysfunction and albuminuria, but to date no one has investigated whether the glomerular endothelial glycocalyx is affected by aldosterone. Invitro, human glomerular endothelial cells exposed to 0.1 nM aldosterone and 145 mMol NaCl exhibited reduced cell surface glycocalyx components (heparan sulfate and syndecan-4) and disrupted shear sensing consistent with damage of the glycocalyx. Invivo, administration of 0.6 μg/g/d of aldosterone (subcutaneous minipump) and 1% NaCl drinking water increased glomerular matrix metalloproteinase 2 activity, reduced syndecan 4 expression, and caused albuminuria. Intravital multiphoton imaging confirmed that aldosterone caused damage of the glomerular endothelial glycocalyx and increased the glomerular sieving coefficient for albumin. Targeting matrix metalloproteinases 2 and 9 with a specific gelatinase inhibitor preserved the glycocalyx, blocked the rise in glomerular sieving coefficient, and prevented albuminuria. Together these data suggest that preservation of the glomerular endothelial glycocalyx may represent a novel strategy for limiting the pathological effects of aldosterone.

This issue of ACTA

This issue of ACTA