Renin-Angiotensin-Aldosterone System Inhibition and Mineralocorticoid Receptor Antagonists: The Overriding Importance of Enablers and Dampers.
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ABSTRACT:
SUBMITTER: Epstein M
PROVIDER: S-EPMC8071656 | biostudies-literature | 2021 Apr
REPOSITORIES: biostudies-literature
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Renin-Angiotensin-Aldosterone System Inhibition and Mineralocorticoid Receptor Antagonists: The Overriding Importance of Enablers and Dampers.
Kidney international reports 20210206 4
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Project description:Because adult podocytes cannot proliferate and are therefore unable to self-renew, replacement of these cells depends on stem/progenitor cells. Although podocyte number is higher after renin-angiotensin-aldosterone system (RAAS) inhibition in glomerular diseases, the events explaining this increase are unclear. Cells of renin lineage (CoRL) have marked plasticity, including the ability to acquire a podocyte phenotype. To test the hypothesis that RAAS inhibition partially replenishes adult podocytes by increasing CoRL number, migration, and/or transdifferentiation, we administered tamoxifen to Ren1cCreERxRs-tdTomato-R CoRL reporter mice to induce permanent labeling of CoRL with red fluorescent protein variant tdTomato. We then induced experimental FSGS, typified by abrupt podocyte depletion, with a cytopathic antipodocyte antibody. RAAS inhibition by enalapril (angiotensin-converting enzyme inhibitor) or losartan (angiotensin-receptor blocker) in FSGS mice stimulated the proliferation of CoRL, increasing the reservoir of these cells in the juxtaglomerular compartment (JGC). Compared with water or hydralazine, RAAS inhibition significantly increased the migration of CoRL from the JGC to the intraglomerular compartment (IGC), with more glomeruli containing RFP+CoRL and, within these glomeruli, more RFP+CoRL. Moreover, RAAS inhibition in FSGS mice increased RFP+CoRL transdifferentiation in the IGC to phenotypes, consistent with those of podocytes (coexpression of synaptopodin and Wilms tumor protein), parietal epithelial cells (PAX 8), and mesangial cells (α8 integrin). These results show that in the context of podocyte depletion in FSGS, RAAS inhibition augments CoRL proliferation and plasticity toward three different glomerular cell lineages.
| S-EPMC5118476 | biostudies-literature
Project description:A collective century of discoveries establishes the importance of the renin angiotensin aldosterone system in maintaining blood pressure, fluid volume and electrolyte homeostasis via autocrine, paracrine and endocrine signaling. While research continues to yield new functions of angiotensin II and angiotensin-(1-7), the gap between basic research and clinical application of these new findings is widening. As data accumulates on the efficacy of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers as drugs of fundamental importance in the treatment of cardiovascular and renal disorders, it is becoming apparent that the achieved clinical benefits is suboptimal and surprisingly no different than what can be achieved with other therapeutic interventions. We discuss this issue and summarize new pathways and mechanisms effecting the synthesis and actions of angiotensin II. The presence of renin-independent non-canonical pathways for angiotensin II production are largely unaffected by agents inhibiting renin angiotensin system activity. Hence, new efforts should be directed to develop drugs that can effectively block the synthesis and/or action of intracellular angiotensin II. Improved drug penetration into cardiac or renal sites of disease, inhibiting chymase the primary angiotensin II forming enzyme in the human heart, and/or inhibiting angiotensinogen synthesis would all be more effective strategies to inhibit the system. Additionally, given the role of angiotensin II in the maintenance of renal homeostatic mechanisms, any new inhibitor should possess greater selectivity of targeting pathogenic angiotensin II signaling processes and thereby limit inappropriate inhibition.
| S-EPMC5648016 | biostudies-literature
Project description:The renin-angiotensin aldosterone system (RAAS) is central to the pathogenesis of cardiovascular disease. RAAS inhibition can reduce blood pressure, prevent target organ damage in hypertension and diabetes, and improve outcomes in patients with heart failure and/or myocardial infarction. This review presents the history of RAAS inhibition including a summary of key heart failure, myocardial infarction, hypertension and atrial fibrillation trials. Recent developments in RAAS inhibition are discussed including implementation and optimization of current drug therapies. Finally, ongoing clinical trials, opportunities for future trials and issues related to the barriers and approvability of novel RAAS inhibitors are highlighted.
| S-EPMC4145865 | biostudies-literature
Project description:Background Previous data suggest that using renin-angiotensin-aldosterone system inhibitors (RAASIs) improves survival in patients with cardiovascular diseases. We sought to investigate the association of different patterns of use of RAASIs on perioperative and 1-year outcomes following carotid revascularization. Methods and Results We investigated patients undergoing carotid revascularization, either with carotid endarterectomy or transfemoral carotid artery stenting, in the VQI (Vascular Quality Initiative) VISION (Vascular Implant Surveillance and Interventional Outcomes Network) data set between 2003 and 2018. We divided our cohort into 3 groups: (1) no history of RAASI intake, (2) preoperative intake only, and (3) continuous pre- and postoperative intake. The final cohort included 73 174 patients; 44.4% had no intake, 50% had continuous intake, and 5.6% had only preoperative intake. Compared with continuous intake, preoperative and no intake were associated with higher odds of postoperative stroke (odds ratio [OR], 1.7 [95% CI, 1.5-1.9]; P<0.001; OR, 1.1 [95% CI, 1.03-1.2]; P=0.010); death (OR, 4.8 [95% CI, 3.8-6.1]; P<0.001; OR, 1.9 [95% CI, 1.6-2.2]; P<0.001); and stroke/death (OR, 2.05 [95% CI, 1.8-2.3]; P<0.001; OR, 1.2 [95% CI, 1.1-1.3]; P<0.001), respectively. At 1 year, preoperative and no intake were associated with higher odds of stroke (hazard ratio [HR], 1.4 [95% CI, 1.3-1.6]; P<0.001; HR, 1.15, [95% CI, 1.08-1.2]; P<0.001); death (HR, 1.7 [95% CI, 1.5-1.9]; P<0.001; HR, 1.3 [95% CI, 1.2-1.4]; P<0.001); and stroke/death (HR, 1.5 [95% CI, 1.4-1.7]; P<0.001; HR, 1.2 [95% CI, 1.17-1.3]; P<0.001), respectively. Conclusions Compared with subjects discontinuing or never starting RAASIs, use of RAASIs before and after carotid revascularization was associated with a short-term stroke and mortality benefit. Future clinical trials examining prescribing patterns of RAASIs should aim to clarify the timing and potential to maximize the protective effects of RAASIs in high-risk vascular patients.
| S-EPMC9496413 | biostudies-literature
Project description:BackgroundMR (mineralocorticoid receptor) antagonists are recommended for patients with resistant hypertension even when circulating aldosterone levels are not high. Although aldosterone activates MR to increase epithelial sodium channel (ENaC) activity, glucocorticoids also activate MR but are metabolized by 11βHSD2 (11β-hydroxysteroid dehydrogenase type 2). 11βHSD2 is expressed at increasing levels from distal convoluted tubule (DCT) through collecting duct. Here, we hypothesized that MR maintains ENaC activity in the DCT2 and early connecting tubule in the absence of aldosterone.MethodsWe studied AS (aldosterone synthase)-deficient (AS-/-) mice, which were backcrossed onto the same C57BL6/J strain as kidney-specific MR knockout (KS-MR-/-) mice. KS-MR-/- mice were used to compare MR expression and ENaC localization and cleavage with AS-/- mice.ResultsMR was highly expressed along DCT2 through the cortical collecting duct (CCD), whereas no 11βHSD2 expression was observed along DCT2. MR signal and apical ENaC localization were clearly reduced along both DCT2 and CCD in KS-MR-/- mice but were fully preserved along DCT2 and were partially reduced along CCD in AS-/- mice. Apical ENaC localization and ENaC currents were fully preserved along DCT2 in AS-/- mice and were not increased along CCD after low salt. AS-/- mice exhibited transient Na+ wasting under low-salt diet, but administration of the MR antagonist eplerenone to AS-/- mice led to hyperkalemia and decreased body weight with higher Na+ excretion, mimicking the phenotype of MR-/- mice.ConclusionsOur results provide evidence that MR is activated in the absence of aldosterone along DCT2 and partially CCD, suggesting glucocorticoid binding to MR preserves sodium homeostasis along DCT2 in AS-/- mice.
| S-EPMC9177775 | biostudies-literature
Project description:ObjectiveTo characterize the dose-exposure-response effect of spironolactone on biomarkers of the classical and alternative arms of the renin-angiotensin-aldosterone system (RAAS) in healthy dogs.AnimalsTen healthy purpose-bred Beagle dogs.ProceduresStudy dogs were randomly allocated to 2 spironolactone dosing groups (2 mg/kg PO q24hr, 4 mg/kg PO q24hr). The dogs received 7-day courses of spironolactone followed by a 14-day washout period in a crossover (AB/BA) design. Angiotensin peptides and aldosterone were measured in serum using equilibrium analysis, and plasma canrenone and 7-α-thiomethyl spironolactone (TMS) were quantified via liquid chromatography-mass spectrometry/mass spectroscopy (LC-MS/MS). Study results were compared before and after dosing and between groups.ResultsFollowing spironolactone treatment, dogs had a significant increase in serum aldosterone concentration (P = 0.07), with no statistical differences between dosing groups. Significant increases in angiotensin II (P = 0.09), angiotensin I (P = 0.08), angiotensin 1-5 (P = 0.08), and a surrogate marker for plasma renin activity (P = 0.06) were detected compared to baseline following spironolactone treatment during the second treatment period only. Overall, changes from baseline did not significantly differ between spironolactone dosages. RAAS analytes were weakly correlated (R < 0.4) with spironolactone dosage and plasma canrenone or plasma TMS. There were no adverse clinical or biochemical effects seen at any spironolactone dosage during treatment.ConclusionsTreatment with spironolactone increased serum aldosterone concentration in healthy dogs and impacted other biomarkers of the classical and alternative arms of the RAAS. There was no difference in effect on the RAAS between 2 and 4 mg/kg/day dosing. Dosage of 4 mg/kg/day was safe and well-tolerated in healthy dogs.
| S-EPMC10890738 | biostudies-literature
Project description:IntroductionTo clarify the efficacy of mineralocorticoid receptor antagonists (MRA) and renin-angiotensin system inhibitors/angiotensin receptor neprilysin inhibitors (RASI/ARNI) in heart failure with mildly reduced ejection fraction (HFmrEF).MethodsThis study assessed the association between these medications and outcomes in HFmrEF using data from the National Taiwan University Hospital-integrated Medical Database. The primary outcome was cardiovascular mortality/heart failure hospitalization (HHF). Inverse probability of treatment weighting balanced baseline patient characteristics. The exposure of primary interest was use of MRA and use of RASI/ARNI, while the non-user group was also likely to receive other heart failure medication treatment.ResultsAmong 2,584 HFmrEF patients, 17% received MRA and 43% received RASI/ARNI. Predictors of MRA use included older age, slightly higher ejection fraction, and lower NT-proBNP level. RASI/ARNI use was predicted by higher BMI, lower NT-proBNP level, normal uric acid and potassium levels. MRA use was not associated with a lower risk of cardiovascular death [hazard ratio = 0.89, 95% confidence interval (CI): 0.78-1.02] or HHF (hazard ratio = 1.01, 95% CI: 0.94-1.09). Conversely, RASI//ARNI use was linked to a lower risk of cardiovascular death (hazard ratio = 0.82, 95% CI: 0.71-0.94) but not HHF (hazard ratio = 0.995, 95% CI: 0.924-1.07). Landmark analysis showed no significant difference in outcomes for follow-up durations exceeding 2 years.ConclusionMRA had a neutral effect on cardiovascular death and HHF, while RASI/ARNI was associated with a lower risk of cardiovascular death. RASI/ARNI may be more beneficial than MRA for HFmrEF patients. Regular re-evaluation is essential to adjust heart failure treatment.
| S-EPMC11671259 | biostudies-literature
Project description:Purpose of reviewThis review summarises the literature data and provides an overview of the role and impact of the use of renin-angiotensin-aldosterone system (RAAS) inhibitors in patients with coronavirus disease 2019 (COVID-19) infection.Recent findingsThe angiotensin-converting enzyme 2 (ACE2) has a key role in the regulation of the RAAS pathway, downregulating angiotensin II and attenuating inflammation, vasoconstriction and oxidative stress. Additionally, it plays an instrumental part in COVID-19 infection as it facilitates the cell entry of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and enables its replication. The use and role of RAAS inhibitors therefore during the COVID-19 pandemic have been intensively investigated. Although it was initially assumed that RAAS inhibitors may relate to worse clinical outcomes and severe disease, data from large studies and meta-analyses demonstrated that they do not have an adverse impact on clinical outcomes or prognosis. On the contrary, some experimental and retrospective observational cohort studies showed a potential protective mechanism, although this effect remains to be seen in large clinical trials.
| S-EPMC9206216 | biostudies-literature
Project description:Chronic activation of the renin-angiotensin-aldosterone system (RAAS) promotes and perpetuates the syndromes of congestive heart failure, systemic hypertension, and chronic kidney disease. Excessive circulating and tissue angiotensin II (AngII) and aldosterone levels lead to a pro-fibrotic, -inflammatory, and -hypertrophic milieu that causes remodeling and dysfunction in cardiovascular and renal tissues. Understanding of the role of the RAAS in this abnormal pathologic remodeling has grown over the past few decades and numerous medical therapies aimed at suppressing the RAAS have been developed. Despite this, morbidity from these diseases remains high. Continued investigation into the complexities of the RAAS should help clinicians modulate (suppress or enhance) components of this system and improve quality of life and survival. This review focuses on updates in our understanding of the RAAS and the pathophysiology of AngII and aldosterone excess, reviewing what is known about its suppression in cardiovascular and renal diseases, especially in the cat and dog.
| S-EPMC6430926 | biostudies-literature
Project description:With the multiplication of COVID-19 severe acute respiratory syndrome cases due to SARS-COV2, some concerns about angiotensin-converting enzyme 1 (ACE1) inhibitors (ACEi) and angiotensin II type 1 receptor blockers (ARB) have emerged. Since the ACE2 (angiotensin-converting enzyme 2) enzyme is the receptor that allows SARS COV2 entry into cells, the fear was that pre-existing treatment with ACEi or ARB might increase the risk of developing severe or fatal severe acute respiratory syndrome in case of COVID-19 infection. The present article discusses these concerns. ACE2 is a membrane-bound enzyme (carboxypeptidase) that contributes to the inactivation of angiotensin II and therefore physiologically counters angiotensin II effects. ACEis do not inhibit ACE2. Although ARBs have been shown to up-regulate ACE2 tissue expression in experimental animals, evidence was not always consistent in human studies. Moreover, to date there is no evidence that ACEi or ARB administration facilitates SARS-COV2 cell entry by increasing ACE2 tissue expression in either animal or human studies. Finally, some studies support the hypothesis that elevated ACE2 membrane expression and tissue activity by administration of ARB and/or infusion of soluble ACE2 could confer protective properties against inflammatory tissue damage in COVID-19 infection. In summary, based on the currently available evidence and as advocated by many medical societies, ACEi or ARB should not be discontinued because of concerns with COVID-19 infection, except when the hemodynamic situation is precarious and case-by-case adjustment is required.
| S-EPMC7172808 | biostudies-literature