eplerenone and Kidney-Diseases

The accompanying special issue reviews the role of eplerenone and spironolactone in the management of various cardiovascular and renal conditions.

Topics: Cardiovascular Diseases; Eplerenone; Humans; Kidney Diseases; Mineralocorticoid Receptor Antagonists; Spironolactone; Treatment Outcome

The renin-angiotensin system (RAS) plays an important role in the pathophysiology of cardiovascular and renal diseases. In chronic kidney disease (CKD), blockade of RAS by angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) has been shown to reduce proteinuria and retard the progression of renal function deterioration. However, aldosterone, another key hormone of the RAS, is not directly targeted by ACEI or ARB. Hyperaldosteronism, apart from promoting sodium and fluid retention, causes inflammation and fibrosis in the heart and kidney. Studies have shown that although plasma aldosterone level shows an initial decrease following ACEI or ARB treatment, it returns to pretreatment level or even increases paradoxically after prolonged treatment. This "aldosterone breakthrough" forms the basis of adding mineralocorticoid receptor (MR) antagonist on top of ACEI or ARB for renal protection. New insights into the pathophysiological role of aldosterone in CKD further expands its potential indications, and there was a growing body of evidence in the past 10 years, which showed a substantial antiproteinuric effect and possibly a considerable renoprotective effect of MR antagonist. Since aldosterone does not act on the efferent glomerular arteriole and has no effect on intraglomerular hemodynamics, the very fact that MR antagonist ameliorates proteinuria sheds light on the physiology of glomerular permeability barrier. This review summarizes the data regarding the theoretical benefit as well as clinical use of MR antagonist in renal diseases.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Eplerenone; Humans; Kidney Diseases; Mineralocorticoid Receptor Antagonists; Renin-Angiotensin System; Spironolactone

Aldosterone, a steroid hormone, has traditionally been viewed as a key regulator of fluid and electrolyte homeostasis, as well as blood pressure, through the activation of mineralocorticoid receptor (MR). However, a number of studies performed in the last decade have revealed an important role of aldosterone/MR in the pathogenesis of renal injury. Aldosterone/MR-induced renal tissue injury is associated with increased renal inflammation and oxidative stress, fibrosis, mesangial cell proliferation, and podocyte injury, probably through genomic and non-genomic pathways. However, our preliminary data have indicated that acute administration of aldosterone or a selective MR antagonist, eplerenone, does not change blood pressure, heart rate, or renal blood flow. These data suggest that aldosterone/MR induces renal injury through mechanisms that are independent of acute changes in systemic and renal hemodynamics. In this review, we will briefly summarize the roles of aldosterone/MR in the pathogenesis of renal injury, focusing on the underlying mechanisms that are independent of systemic and renal hemodynamic changes.

Topics: Aldosterone; Animals; Blood Pressure; Electrolytes; Eplerenone; Homeostasis; Humans; Kidney; Kidney Diseases; Mineralocorticoid Receptor Antagonists; Oxidative Stress; Rats; Receptors, Mineralocorticoid; Renal Circulation; Spironolactone

Topics: Aldosterone; Animals; Chronic Disease; Eplerenone; Humans; Kidney Diseases; Metabolic Syndrome; Mineralocorticoid Receptor Antagonists; Podocytes; Proteinuria; Receptors, Mineralocorticoid; Risk Factors; Spironolactone

There is increasing evidence indicating the roles of aldosterone and mineralocorticoid receptor (MR) in the pathogenesis of renal injury. In rats, chronic treatment with aldosterone and salt results in severe proteinuria and renal tissue injury, characterized by glomerulosclerosis and tubulointerstitial fibrosis. Aldosterone-induced renal tissue injury is associated with increases in reactive oxygen species (ROS) levels and activation of mitogen-activated protein kinases (MAPKs) or Rho-kinase. Treatment with a selective MR antagonist, eplerenone, prevents aldosterone-induced increases in ROS levels and MAPK activity and ameliorates renal injury. In vitro studies have revealed that MR is highly expressed in glomerular mesangial cells (RMCs), podocytes, and renal interstitial fibroblasts. In these renal cells, aldosterone induces cellular injury through NADPH oxidase-dependent ROS production and activation of MAPKs or Rho-kinase. Such aldosterone-induced renal cellular injury is markedly attenuated by treatment with eplerenone. These data suggest that aldosterone induces renal injury via activation of MR through mechanisms that cannot be simply explained by changes in blood pressure. In this review, we summarized recent findings on the roles of aldosterone and MR in the pathogenesis of renal injury with particular emphasis on potential underlying mechanisms.

Topics: Aldosterone; Animals; Eplerenone; Humans; Kidney; Kidney Diseases; Mitogen-Activated Protein Kinases; Reactive Oxygen Species; Receptors, Mineralocorticoid; rho-Associated Kinases; Spironolactone

Recent clinical and pre-clinical studies have indicated the utility of mineralocorticoid receptor (MR) antagonists in renal injury. We have demonstrated in rats that chronic treatment with aldosterone results in severe proteinuria and renal injury, characterized by glomerular changes, tubulointerstitial fibrosis, and collagen accumulation. We also observed increased reactive oxygen species (ROS) generation and mitogen-activated protein kinases (MAPKs) activity in renal cortical tissues. Treatment with a selective MR antagonist, eplerenone, prevented elevation of ROS levels and MAPK activity, as well as ameliorating renal injury. In vitro studies revealed that MRs are highly expressed in rat glomerular mesangial cells (RMC) and rat renal fibroblasts. In RMC, aldosterone induces cellular injuries through NADPH oxidase-dependent ROS production and/or MAPK activation. Aldosterone-induced renal cellular injuries were markedly attenuated by treatment with eplerenone. These data suggest that aldosterone induces renal injury through activation of MRs and support the notion that MR blockade has beneficial effects on aldosterone-dependent renal injury through mechanisms that cannot be simply explained by hemodynamic changes. In this review, we summarized our recent findings pertaining to the roles of aldosterone and MRs in the pathogenesis of renal injury. Potential molecular mechanisms responsible for aldosterone/MR-induced renal injury were also discussed.

Topics: Aldosterone; Animals; Cell Proliferation; Cell Shape; Cells, Cultured; Collagen; Eplerenone; Fibroblasts; Fibrosis; Humans; Kidney; Kidney Diseases; Mesangial Cells; Mineralocorticoid Receptor Antagonists; Mitogen-Activated Protein Kinases; Rats; Reactive Oxygen Species; Receptors, Mineralocorticoid; Spironolactone

Topics: Aldosterone; Animals; Body Water; Disease Models, Animal; Eplerenone; Humans; Hypertension; Kidney Diseases; Mineralocorticoid Receptor Antagonists; Potassium; Proteinuria; Receptors, Mineralocorticoid; Sodium; Spironolactone

Activation of the renin-angiotensin-aldosterone system is associated with unsatisfactory outcomes in patients with hypertension and heart failure in that activation of this system is correlated strongly with both the incidence and extent of end-organ damage. Despite the availability of the angiotensin converting enzyme inhibitors (ACEi) and the angiotensin receptor blockers (ARB), unblocked aldosterone levels remain an important risk factor for cardiovascular disease progression. New preclinical data generated over the last few years strongly supports the hypothesis that aldosterone has important deleterious effects on the cardiovascular system independent of the classical action of this hormone on renal epithelial cells. The new selective aldosterone blocker, eplerenone, has been shown to produce significant cardioprotective and renoprotecive effects in experimental models of cardiovascular disease. Early clinical studies suggests that eplerenone may have important therapeutic benefit in the treatment of hypertension and heart failure post-myocardial infarction (post-MI).

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiovascular System; Disease Models, Animal; Dogs; Eplerenone; Heart Injuries; Humans; Kidney Diseases; Mineralocorticoid Receptor Antagonists; Rats; Renin-Angiotensin System; Spironolactone

Interruption of the renin-angiotensin-aldosterone system (RAAS) at different levels is target-organ protective in several disease states; however, complete blockade is unlikely to be achieved due to escape mechanisms whenever blockade is attempted, incomplete knowledge of the role of all elements of the RAAS, and lack of pharmacotherapy against some elements that have been shown to contribute to disease states. Aldosterone has been overlooked as a mediator of RAAS escape and a key factor in target-organ injury despite the use of available RAAS blockers. Aldosterone is thought to play a role in the development of hypertension, alteration in vascular structure, vascular smooth muscle hypertrophy, endothelial dysfunction, structural renal injury, proteinuria, left ventricular remodeling, collagen synthesis, and myocardial fibrosis. Aldosterone receptor antagonists have been shown to antagonize all these effects in experimental models. Clinical trials with aldosterone antagonists showed an improvement in survival and left ventricular mass index in patients with congestive heart failure, and a reduction in urinary protein excretion and left ventricular mass index in patients with type 2 diabetes and early nephropathy who developed aldosterone synthesis escape. Consequently, aldosterone receptor antagonists may have specific benefits for reducing target-organ injury, particularly if there is evidence of RAAS escape.

Topics: Aldosterone; Cardiovascular Diseases; Eplerenone; Humans; Kidney Diseases; Mineralocorticoid Receptor Antagonists; Renin-Angiotensin System; Spironolactone

Aldosterone contributes to hypertension, cardiac and vascular remodeling, and heart failure. The significant risk reduction provided by the addition of spironolactone to standard therapy in patients with severe heart failure has renewed interest in aldosterone blockade.. This review describes recent clinical studies of eplerenone, a selective aldosterone blocker, in patients with hypertension.. In a 16-week study, eplerenone was more effective than placebo or losartan in lowering systolic blood pressure (BP) and diastolic BP in black patients with mild to moderate hypertension. The BP-lowering efficacy of eplerenone was similar in blacks and whites. In a separate study in patients whose BP was controlled inadequately by angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, addition of eplerenone significantly reduced systolic BP, and to a lesser extent, diastolic BP. There were no significant changes in potassium levels in this study. Eplerenone increased active renin and aldosterone levels, indicating that it blocks the renin-angiotensin-aldosterone system. Gynecomastia, or breast tenderness, was uncommon and occurred at a rate comparable to placebo.. Eplerenone is a selective aldosterone blocker that effectively lowers BP in both white and black patients with hypertension and provides meaningful further antihypertensive efficacy when added to patients whose hypertension is inadequately controlled by angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers.

Topics: Aldosterone; Antihypertensive Agents; Black People; Blood Pressure; Cardiovascular Diseases; Clinical Trials as Topic; Eplerenone; Humans; Hypertension; Kidney Diseases; Losartan; Mineralocorticoid Receptor Antagonists; Potassium; Renin-Angiotensin System; Spironolactone

Eplerenone, an aldosterone receptor antagonist from Searle is being developed as a potential treatment for renal disease, congestive heart failure and hypertension. It is in phase III clinical trials 1312280], [353548]. Monsanto (now Pharmacia) expects to launch the compound in 2002 [370466]. Pharmacia anticipates filing for congestive heart failure in 2002 [374505]. A global phase III survival trial was initiated in the US and approximately 30 other countries in January 2000. The trial will evaluate whether eplerenone can reduce the rate of mortality in patients who have recently had a heart attack that resulted in a diagnosis of heart failure 13535481.

Topics: Animals; Antihypertensive Agents; Clinical Trials as Topic; Eplerenone; Heart Failure; Humans; Hypertension; Kidney Diseases; Mineralocorticoid Receptor Antagonists; Spironolactone

Although inhibitors of the renin-angiotensin system are effective as first-line antihypertensive drugs in hypertensive patients with chronic kidney disease, they cannot completely prevent the progression of renal injury. Many animal studies, including our own, and a few human studies suggest that mineralocorticoid receptor blockade could inhibit the ongoing renal damage in chronic kidney disease. Thus, we designed this double-blinded, randomized, placebo-controlled trial to evaluate the antialbuminuric effect of a low dose (50 mg day(-1)) of the mineralocorticoid receptor antagonist eplerenone. The study subjects will include 340 hypertensive patients (blood pressure: 130-180/80-100 mm Hg) with albuminuria (urinary albumin/creatinine ratio: 30-600 mg g(-1) in the first morning void urine), who are treated with an inhibitor of the renin-angiotensin system. Other classes of antihypertensive drugs may be added as needed to achieve the target blood pressure (<130/80 mm Hg). The primary study end point is the change in the urinary albumin/creatinine ratio after a 1-year study period. This trial is expected to show whether a low dose of mineralocorticoid receptor antagonists can exert an antialbuminuric effect in patients with chronic kidney disease.

Topics: Adult; Aged; Albuminuria; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Chronic Disease; Creatine; Drug Therapy, Combination; Eplerenone; Female; Humans; Hypertension; Kidney; Kidney Diseases; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Sodium Chloride, Dietary; Spironolactone; Young Adult

The influence of renal impairment on the pharmacokinetics of eplerenone following single and multiple dosing was evaluated. Subjects (n = 64) were stratified based on creatinine clearance values as follows: renal impairment (mild, moderate, severe), hemodialysis, and normal matches. Subjects received a single dose of eplerenone 100 mg on day 1 and then received 100 mg once daily on days 3 to 8. There were no statistically significant differences between any of the renal impairment groups and their matched-normal groups for area under the curve (AUC), C(max), or CL/F or CL/F/WT following either single or multiple dosing (P > or = .093). The inactive metabolite and inactive ring-opened form displayed greater AUCs in renal impairment. Hemodialysis removed approximately 10% of the eplerenone dose. Eplerenone 100 mg once daily was well tolerated in all groups. Considering that renal function had no significant effects on eplerenone CL/F and that eplerenone metabolites are inactive, no dose adjustment appears necessary in patients with renal dysfunction.

Topics: Administration, Oral; Adult; Aged; Area Under Curve; Creatinine; Eplerenone; Female; Humans; Hyperkalemia; Kidney Diseases; Male; Metabolic Clearance Rate; Middle Aged; Mineralocorticoid Receptor Antagonists; Renal Dialysis; Spironolactone

The beneficial effects of mineralocorticoid receptor (MR) antagonists (MRAs) for various kidney diseases are established. However, the underlying mechanisms of kidney injury induced by MR activation remain to be elucidated. We recently reported aldosterone-induced enhancement of proteoglycan expression in mitral valve interstitial cells and its association with fibromyxomatous valvular disorder. As the expression of certain proteoglycans is elevated in several kidney diseases, we hypothesized that proteoglycans mediate kidney injury in the context of aldosterone/MR pathway activation. We evaluated the proteoglycan expression and tissue injury in the kidney and isolated glomeruli of uninephrectomy/aldosterone/salt (NAS) mice. The MRA eplerenone was administered to assess the role of the MR pathway. We investigated the direct effects of biglycan, one of the proteoglycans, on macrophages using isolated macrophages. The kidney samples from NAS-treated mice showed enhanced fibrosis and increased expression of biglycan accompanying glomerular macrophage infiltration and enhanced expression of TNF-α, iNOS, Nox2, CCL3 (C-C motif chemokine ligand 3), and phosphorylated NF-κB. Eplerenone blunted these changes. Purified biglycan stimulated macrophages to express TNF-α, iNOS, Nox2, and CCL3. This was prevented by a toll-like receptor 4 (TLR4) or NF-κB inhibitor, indicating that biglycan stimulation is dependent on the TLR4/NF-κB pathway. We identified the proteoglycan biglycan as a novel target of MR involved in MR-induced glomerular injury and macrophage infiltration via a biglycan/TLR4/NF-κB/CCL3 cascade.

Topics: Aldosterone; Animals; Biglycan; Eplerenone; Kidney Diseases; Mice; Mineralocorticoid Receptor Antagonists; NF-kappa B; Receptors, Mineralocorticoid; Signal Transduction; Sodium Chloride, Dietary; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Mineralocorticoid receptor antagonist (MRA) when combined with either angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) may provide additional benefits of cardiovascular and kidney disease risk reduction in patients with diabetic kidney disease (DKD) and hypertension. We evaluated the effectiveness of combination therapy (MRAs, either spironolactone or eplerenone, plus ACEI/ARB) compared with monotherapy (ACEI/ARB only) in patients with DKD and hypertension.. Retrospective cohort study was performed in patients (age ≥ 18 years) with hypertension, diabetes, and albuminuria between 2008 and 2018 within an integrated health system. MRA with ACEI/ARB compared to ACEI/ARB alone was evaluated on composite of cardiovascular events, progression to end-stage kidney disease, or all-cause mortality. Hyperkalemia was compared as a safety outcome.. We identified 1282 patients who received MRAs with ACEI/ARBs and 5484 patients who received ACEI/ARBs alone. Median exposure time for combination therapy was 126 days. The rates per 100 person-years of cardiovascular, kidney, or all-cause mortality outcomes were 12.2 and 9.2 for combination therapy and monotherapy, respectively (hazard ratios = 1.24, 95% Confidence Interval (CI):0.94, 1.63). Patients receiving combination therapy had greater reduction in urine albumin-to-creatinine ratio compared with monotherapy (Mean reduction: 823 and 585 mg/g; p < 0.001, respectively). Hyperkalemia was more frequent in combination therapy versus monotherapy (22.3 vs. 10.9 per 100 person-years for combination and monotherapy, respectively; hazard ratios = 1.78, 95%CI: 1.42, 2.24).. Among patients with DKD and hypertension, the short-term use of MRAs, either spironolactone or eplerenone, in combination with ACEI/ARBs, was not associated with lower risk of cardiovascular or kidney outcomes compared with ACEI/ARB monotherapy. The risk of hyperkalemia and the short duration of combination therapy may suggest a real-world clinical challenge for MRA with ACEI/ARB combination therapy.

Topics: Adolescent; Adult; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetic Nephropathies; Drug Therapy, Combination; Eplerenone; Humans; Hypertension; Kidney Diseases; Mineralocorticoid Receptor Antagonists; Retrospective Studies; Spironolactone; Treatment Outcome

The fact that mineralocorticoid receptor antagonists reduce structural and functional alterations induced by cyclosporine A (CsA) indicates that aldosterone plays a key role in chronic CsA nephrotoxicity. We and other researchers have reported local renal aldosterone synthesis. To investigate local renal aldosterone's role in chronic CsA nephrotoxicity, we evaluated the effect of eplerenone (Epl) on renal structural damage and renal dysfunction in adrenalectomized (ADX) rats, and assessed whether the therapeutic benefit was associated with reduction of transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF), plasminogen activator inhibitor type 1 (PAI-1) and collagen I (COL-I) expression.. Male Sprague-Dawley rats fed a normal-sodium diet were divided in four groups: sham-ADX, ADX, CsA, or Epl. Rats in the ADX, CsA and Epl groups were adrenalectomized first. Aldosterone, sodium and potassium levels in serum and urine were measured on the second day. Two weeks later, vehicle (sham-ADX and ADX group), CsA (25mg/kg/d), or CsA and Epl (100 mg/ kg/d) combination was administrated, respectively. After six weeks, urinary protein, creatinine clearance (Ccr), tubulointerstitial fibrosis (TIF), aldosterone level in kidney, and renal aldosterone synthase CYP11B2, COL-I, TGF-β1, CTGF and PAI-1 gene expression levels were determined.. On the second day after surgery, adrenalectomized rats showed undetectable aldosterone with natriuresis, hyponatremia, decreased urinary potassium excretion and hyperpotassemia. CsA reduced Ccr, induced urinary proteins and up-regulated COL-I, TGF-β1, CTGF and PAI-1 gene expression with a significant development of TIF. Eplerenone administration prevented TIF and COL-I, TGF-β1 and PAI-1 up-regulation but did not improve renal function.. Our results suggest local renal aldosterone is an important mediator of renal injury induced by CsA.

Topics: Adrenalectomy; Aldosterone; Animals; Chronic Disease; Cyclosporine; Cytochrome P-450 CYP11B2; Disease Models, Animal; Electrolytes; Eplerenone; Fibrosis; Kidney; Kidney Diseases; Male; Potassium; Rats, Sprague-Dawley; RNA, Messenger; Sodium; Spironolactone

Besides the well-known roles of aldosterone as a mineralocorticoid in regulating homeostasis of electrolytes and volume, recent studies revealed that it is also a potent proinflammation factor inducing reactive oxygen species and up-regulating a panel of fibrosis related genes. Under pathological circumstances, excessive aldosterone is involved in a lot of chronic diseases, including hypertension, cardiac fibrosis, congestive heart failure, ventricular remodeling, and diabetic nephropathy. Therefore, the inhibition of aldosterone synthase (CYP11B2), which is the pivotal enzyme in aldosterone biosynthesis, was proposed as a superior approach. Expected pharmacodynamic effects have been demonstrated in both animal models and clinical trials after the application of CYP11B2 inhibitors. The importance of selectivity over other steroidogenic CYP enzymes, in particular 11β-hydroxylase (CYP11B1), was also revealed. Recently, much more selective CYP11B2 inhibitors have been reported, which could be promising drug candidates for the treatment of aldosterone related diseases.

Topics: Aldosterone; Animals; Benzimidazoles; Cardiovascular Diseases; Cytochrome P-450 CYP11B2; Fadrozole; Humans; Indans; Indoles; Kidney Diseases; Mineralocorticoids; Naphthalenes; Quinolines; Receptors, Mineralocorticoid

Pharmacological blockade of the mineralocorticoid receptor (MR) ameliorates end-organ damage in chronic heart failure. However, the clinical use of available steroidal MR antagonists is restricted because of concomitant hyperkalemia especially in patients with diminished kidney function. We have recently identified a novel nonsteroidal MR antagonist, finerenone, which uniquely combines potency and selectivity toward MR. Here, we investigated the tissue distribution and chronic cardiorenal end-organ protection of finerenone in comparison to the steroidal MR antagonist, eplerenone, in 2 different preclinical rat disease models. Quantitative whole-body autoradiography revealed that [C]-labeled finerenone equally distributes into rat cardiac and renal tissues. Finerenone treatment prevented deoxycorticosterone acetate-/salt-challenged rats from functional as well as structural heart and kidney damage at dosages not reducing systemic blood pressure. Finerenone reduced cardiac hypertrophy, plasma prohormone of brain natriuretic peptide, and proteinuria more efficiently than eplerenone when comparing equinatriuretic doses. In rats that developed chronic heart failure after coronary artery ligation, finerenone (1 mg·kg·d), but not eplerenone (100 mg·kg·d) improved systolic and diastolic left ventricular function and reduced plasma prohormone of brain natriuretic peptide levels. We conclude that finerenone may offer end-organ protection with a reduced risk of electrolyte disturbances.

Topics: Animals; Autoradiography; Cardiomegaly; Disease Models, Animal; Eplerenone; Heart Failure; Kidney Diseases; Male; Mineralocorticoid Receptor Antagonists; Naphthyridines; Natriuretic Peptide, Brain; Peptide Fragments; Rats; Rats, Sprague-Dawley; Rats, Wistar; Spironolactone; Tissue Distribution

Hypertension is a major risk factor for the development and progression of chronic kidney disease (CKD). Mineralocorticoid receptor antagonists (MRAs) are effective in the management of resistant hypertension but are not widely used in CKD because of the risk of hyperkalemia. We retrospectively evaluated the long-term effects and safety of MRAs added to a pre-existing antihypertensive regimen in subjects with resistant hypertension associated with stage 3 CKD. In all, 32 patients were treated with spironolactone and 4 with eplerenone for a median follow-up of 312 days. MRAs induced a significant decrease in systolic blood pressure from 162±22 to 138±14 mm Hg (P<0.0001) and in diastolic blood pressure from 87±17 to 74±12 mm Hg (P<0.0001). Serum potassium increased from 4.0±0.5 to 4.4±0.5 mEq l(-1) (P=0.0001), with the highest value being 5.8 mEq l(-1). The serum creatinine increased from 1.5±0.3 to 1.8±0.5 mg dl(-1) (P=0.0004) and the estimated glomerular filtration rate decreased from 48.6±8.7 to 41.2±11.5 ml min(-1) per 1.73 m(2) (P=0.0002). One case of acute renal failure and three cases of significant hyperkalemia occurred. MRAs significantly reduced blood pressure in subjects with resistant hypertension associated with stage 3 CKD, although close biochemical monitoring is recommended because of an increased risk of hyperkalemia and worsening of renal function.

Topics: Acute Kidney Injury; Aged; Alabama; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biomarkers; Blood Pressure; Chi-Square Distribution; Chronic Disease; Creatinine; Diuretics; Drug Resistance; Drug Therapy, Combination; Eplerenone; Female; Glomerular Filtration Rate; Humans; Hyperkalemia; Hypertension; Kidney; Kidney Diseases; Logistic Models; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Potassium; Retrospective Studies; Risk Assessment; Risk Factors; Spironolactone; Time Factors; Treatment Outcome

Several factors, including mineralocorticoids, have been implicated in the renal damage associated with hypertension. Peroxisome proliferator activated receptor gamma (PPAR-γ) agonists improve renal damage associated with different pathologies. Therefore, our hypothesis was that mineralocorticoid receptor blockade ameliorates renal damage associated with hypertension and that this improvement may be mediated by PPAR-γ. Spontaneously hypertensive rats (SHR) were treated with either vehicle or eplerenone, a mineralocorticoid receptor antagonist, at two different doses: 30 and 100 mg/kg/day for 10 weeks. Age-matched Wistar Kyoto rats (WKY) were used as a normotensive reference group. SHR showed tubulointersticial fibrosis and mild tubular atrophy. These alterations were accompanied by increases in renal cortex gene expression of transforming growth factor beta (TGF-β) connective tissue growth factor (CTGF) and phosphorylated Smad2 protein levels, factors involved in the fibrotic response. Interleukin 1-beta (IL-1β) and tumor necrosis factor alpha (TNF-α) gene expression were also increased. By contrast, lysyl oxidase (LOX) expression and PPAR-γ protein levels were decreased in SHR as compared with normotensive animals. Only the high dose of eplerenone was able to reduce blood pressure and partially prevent LOX down-regulation in SHR. Both eplerenone doses significantly ameliorated interstitial fibrosis and tubular atrophy, reduced TGF-β, CTGF and cytokine gene expression, and decreased Smad2 activation, while normalizing PPAR-γ protein levels.. Mineralocorticoid receptor activation participates in hypertension-associated renal damage. This effect seems to involve stimulation of both fibrotic and inflammatory processes mediated (at least in part) by a down-regulation of PPAR-γ that can favour an up-regulation of the TGF-β/Smad signalling pathway.

Topics: Animals; Blood Pressure; Connective Tissue Growth Factor; Cytokines; Down-Regulation; Eplerenone; Gene Expression; Hypertension; Kidney Cortex; Kidney Diseases; Male; Mineralocorticoid Receptor Antagonists; PPAR gamma; Protein-Lysine 6-Oxidase; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Mineralocorticoid; Signal Transduction; Smad2 Protein; Spironolactone; Up-Regulation

To investigate the protective effects of eplerenone on adriamycin-induced renal injury and the possible mechanisms involved, 36 male Sprague-Dawley rats were randomly divided into control group, adriamycin nephropathy (AN) group and eplerenone-treated group (100 mg·kg(-1)·d(-1) eplerenone). Blood pressure, 24-h urinary protein, serum potassium, sodium and creatinine were measured 28 days after adriamycin injection (a single tail intravenous injection of 6.5 mg/kg adriamycin). The morphological changes of renal tissues were observed by light and electron microscopy. Immunohistochemistry and Western blotting were performed to examine the expression of TGF-β(1) and desmin in renal cortex. The results showed that 28 days after adriamycin injection, there were no significant changes in the level of serum potassium, sodium, creatinine concentrations and blood pressure values in the rats of the three groups. Meanwhile, the 24-h proteinuria excretion in the AN group was significantly higher than that in the control group (P<0.01), but that in the eplerenone-treated group was substantially reduced when compared with that in the AN group (P<0.05). Mild mesangial cell proliferation and matrix expansion, diffuse deformation and confluence of foot processes in podocytes were found in the AN group. By contrast, rats in the eplerenone-treated group exhibited obvious attenuation of these morphological lesions. The protein expression of TGF-β(1) and desmin in the AN group was markedly up-regulated in contrast to that in the control group (P<0.01), whereas that in the eplerenone-treated group was much lower than in the AN group (P<0.05). It was concluded that eplerenone may ameliorate the proteinuria and the development of pathological alteration in adriamycin-induced nephropathy presumably via the inhibition of cytokine release, and restore the morphology of podocytes independent of its blood pressure-lowing effects.

Topics: Animals; Cytokines; Down-Regulation; Doxorubicin; Eplerenone; Kidney Diseases; Kidney Glomerulus; Male; Mineralocorticoid Receptor Antagonists; Podocytes; Protective Agents; Proteinuria; Rats; Rats, Sprague-Dawley; Spironolactone

We have discovered a novel class of nonsteroidal pyrazoline antagonists of the mineralocorticoid receptor (MR) that show excellent potency and selectivity against other nuclear receptors. Early analogues were poorly soluble and had a propensity to inhibit the hERG channel. Remarkably, both of these challenges were overcome by incorporation of a single carboxylate moiety. Structural modification of carboxylate-containing lead R-4g with a wide range of substituents at each position of the pyrazoline ring resulted in R-12o, which shows excellent activity against MR and reasonable pharmacokinetic profile. Introduction of conformational restriction led to a novel series characterized by exquisite potency and favorable steroid receptor selectivity and pharmacokinetic profile. Oral dosing of 3S,3aR-27d (PF-3882845) in the Dahl salt sensitive preclinical model of salt-induced hypertension and nephropathy showed blood pressure attenuation significantly greater than that with eplerenone, reduction in urinary albumin, and renal protection. As a result of these findings, 3S,3aR-27d was advanced to clinical studies.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Cell Line, Tumor; Chlorobenzenes; Crystallography, X-Ray; Humans; Hypertension; Indazoles; Indenes; Kidney Diseases; Male; Mineralocorticoid Receptor Antagonists; Models, Molecular; Molecular Conformation; Nitriles; Radioligand Assay; Rats; Rats, Inbred Dahl; Rats, Sprague-Dawley; Stereoisomerism; Structure-Activity Relationship

1. Nephropathy and elevated plasma aldosterone concentrations (PAC) have been observed in (pro)renin receptor transgenic (TG) rats. In the present study, we hypothesized that PAC and/or mineralocorticoid receptor contribute to the nephropathy of TG rats. To test this hypothesis, the effects of a high-sodium (8% NaCl) diet and heminephrectomy on PAC were examined. 2. Feeding of the high-sodium diet for 12 weeks similarly decreased PAC in TG and wild-type (WT) rats. Heminephrectomy further reduced PAC in TG rats fed a high-sodium diet, but had no effect on PAC in WT rats fed a high-sodium diet. 3. Next, the effects of eplerenone (125 mg/kg per day) and dietary salt restriction (0.36% NaCl diet) on proteinuria and renal morphology were examined in rats fed a high-sodium diet or subjected to heminephrectomy. Both eplerenone and dietary sodium restriction significantly reduced the arterial pressure of TG rats, but had no effect in WT rats. In TG rats, treatment with eplerenone significantly decreased urinary protein excretion, but dietary sodium restriction did not. 4. Nephrin and podocin mRNA levels, as determined by real-time quantitative reverse transcription-polymerase chain reaction, were significantly lower in TG rats than in WT rats. In TG rats, eplerenone treatment significantly increased nephrin mRNA levels, but not podocin mRNA levels. Dietary salt restriction significantly increased mRNA levels of both nephrin and podocin. Although zonula occludens (ZO)-1 mRNA levels were similar in both WT and TG rats, eplerenone treatment significantly decreased ZO-1 mRNA levels in TG rats. 5. The results of the present study suggest that the improvement in proteinuria following eplerenone treatment is independent of its effects on sodium balance and may be mediated by effects on the expression of slit diaphragm proteins.

Topics: Aldosterone; Animals; Eplerenone; Humans; Kidney Diseases; Mineralocorticoid Receptor Antagonists; Nephrectomy; Prorenin Receptor; Rats; Rats, Transgenic; Receptors, Cell Surface; Sodium Chloride, Dietary; Spironolactone

Topics: Adult; Aged; Aged, 80 and over; Chronic Disease; Clinical Trials as Topic; Eplerenone; Female; Humans; Hyperkalemia; Hypertension; Kidney Diseases; Male; Middle Aged; Spironolactone; Young Adult

Topics: Aldosterone; Eplerenone; Humans; Hypertension; Kidney Diseases; Mineralocorticoid Receptor Antagonists; Nephrology; Spironolactone

We hypothesized that combination treatment with the mineralocorticoid receptor antagonist eplerenone and the calcium channel blocker amlodipine elicits better renoprotective effects than monotherapy with either drug, via different mechanisms in Dahl salt-sensitive (DS) hypertensive rats. DS rats were fed a high-salt diet (4% NaCl) for 10 wk and were treated with vehicle (n = 12), eplerenone (50 mg x kg(-1) x day(-1), p.o., n = 12), amlodipine (3 mg x kg(-1) x day(-1), p.o., n = 12), or eplerenone plus amlodipine (n = 12) after 2 wk of salt feeding. Vehicle-treated DS rats developed proteinuria, which was attenuated by eplerenone or amlodipine. Interestingly, eplerenone attenuated the glomerulosclerosis and podocyte injury, but amlodipine did not. Conversely, treatment with amlodipine markedly improved interstitial fibrosis, while the effect of eplerenone was minimal. Combination treatment markedly improved proteinuria, glomerulosclerosis, podocyte injury, and interstitial fibrosis in DS rats. Renal hypoxia estimated by pimonidazole, vascular endothelial growth factor expression, and density of peritubular endothelial cells was exacerbated by salt feeding. Amlodipine, either as monotherapy or in combination, ameliorated the renal hypoxia, whereas eplerenone treatment had no effect. In conclusion, both eplerenone and amlodipine attenuated renal injuries in high salt-fed DS rats, but the targets for renoprotection differed between these two drugs, with eplerenone predominantly acting on glomeruli and amlodipine acting on interstitium. The combination of eplerenone and amlodipine improved renal injury more effectively than either monotherapy in high salt-fed DS rats, presumably by achieving their own renoprotective effects.

Topics: Amlodipine; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cell Hypoxia; Creatinine; Drug Therapy, Combination; Endothelial Cells; Eplerenone; Fibrosis; Hypertension; Immediate-Early Proteins; Kidney Diseases; Kidney Glomerulus; Kidney Tubules; Male; Mineralocorticoid Receptor Antagonists; Podocytes; Protein Serine-Threonine Kinases; Proteinuria; Rats; Rats, Inbred Dahl; Receptors, Mineralocorticoid; Sodium Chloride, Dietary; Spironolactone; Time Factors; Vascular Endothelial Growth Factor A

Aldosterone is implicated in the pathogenesis of proteinuria and chronic kidney disease. We previously demonstrated the contribution of elevated serum aldosterone in the early nephropathy of SHR/NDmcr-cp (SHR/cp), a rat model of metabolic syndrome. In the present study, we investigated the effect of salt loading on renal damage in SHR/cps and explored the underlying mechanisms. SHR/cps fed a high-sodium diet for 4 weeks developed severe hypertension, massive proteinuria, and advanced renal lesions. High salt also worsened glomerular podocyte impairment. Surprisingly, selective mineralocorticoid receptor (MR) antagonist eplerenone dramatically ameliorated the salt-induced proteinuria and renal injury in SHR/cps. Although salt loading reduced circulating aldosterone, it increased nuclear MR and expression of aldosterone effector kinase Sgk1 in the kidney. Gene expressions of transforming growth factor-beta1 and plasminogen activator inhibitor-1 were also enhanced in the kidneys of salt-loaded SHR/cps, and eplerenone completely inhibited these injury markers. To clarify the discrepancy between decreased aldosterone and enhanced MR signaling by salt, we further investigated the role of oxidative stress, a putative key factor mediating salt-induced tissue damage. Interestingly, antioxidant Tempol attenuated the salt-evoked MR upregulation and Sgk1 induction and alleviated proteinuria and renal histological abnormalities, suggesting the involvement of oxidative stress in salt-induced MR activation. MR activation by salt was not attributed to increased serum corticosterone or reduced 11beta-hydroxysteroid dehydrogenase type 2 activity. In conclusion, sodium loading exacerbated proteinuria and renal injury in metabolic syndrome rats. Salt reduced circulating aldosterone but caused renal MR activation at least partially via induction of oxidative stress, and eplerenone effectively improved the nephropathy.

Topics: Aldosterone; Animals; Antioxidants; Cyclic N-Oxides; Disease Models, Animal; Eplerenone; Hypertension; Kidney Diseases; Male; Metabolic Syndrome; Obesity; Oxidative Stress; Rats; Rats, Inbred SHR; Rats, Mutant Strains; Receptors, Cell Surface; Receptors, Leptin; Receptors, Mineralocorticoid; Renin; Sodium Chloride, Dietary; Spin Labels; Spironolactone