Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is increasing evidence demonstrating that the renoprotective effects of mineralocorticoid receptor (MR) blockade are independent of the effects exerted by renin-angiotensin inhibitors. MR is expressed not only in tubular cells but also in other renal cells including glomerular mesangial cells, podocytes, and renal interstitial fibroblasts. Animal experiments have shown that MR blockers prevent aldosterone-induced proteinuria, glomerular injury, and tubulointerstitial fibrosis. In vitro studies have also demonstrated that MR blockers inhibit aldosterone-induced renal cell damage. Recent clinical studies have shown that treatment with MR blockers attenuates the development of proteinuria in patients with chronic kidney disease (CKD) and hypertension, independent of changes in blood pressure. In some cases, MR blockers elicit potent renoprotective effects in conditions where aldosterone levels are not elevated. These data suggest that treatment with MR blockers may possibly present an effective therapeutic strategy for patients with CKD.
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PMID:Drug discovery for overcoming chronic kidney disease (CKD): pharmacological effects of mineralocorticoid-receptor blockers. 1915 33

Chronic transplant dysfunction (CTD) is the leading cause of long-term renal allograft loss and is characterized by specific histological lesions including transplant vasculopathy, interstitial fibrosis, and focal glomerulosclerosis. Increasing evidence indicates that aldosterone is a direct mediator of renal damage via the mineralocorticoid receptor (MR). The MR antagonist spironolactone is renoprotective in native chronic kidney disease, but its effects on CTD are unknown. We studied the effects of spironolactone treatment on CTD development in the Dark Agouti-to-Wistar-Furth renal allograft transplant model, by treatment with 20 mg/kg spironolactone or vehicle daily by oral gavage from 2 days before transplantation (donors and recipients) throughout the experiment (12 wk, recipients). Dark Agouti-to-Dark Agouti isografts served as negative controls. Spironolactone significantly ameliorated the development of transplant vasculopathy in allografts by reducing the number of affected intrarenal arteries. In addition, spironolactone treatment showed a trend toward reduced proteinuria and focal glomerulosclerosis, and significantly reduced glomerular macrophage influx. However, spironolactone treatment did not affect interstitial fibrosis, interstitial macrophage influx, creatinine clearance, and systolic blood pressure. We conclude that spironolactone selectively ameliorates transplant vasculopathy and glomerular lesions in renal CTD in rats. These results suggest that spironolactone may have renoprotective potential as an adjunct treatment in renal transplantation to ameliorate CTD.
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PMID:Spironolactone ameliorates transplant vasculopathy in renal chronic transplant dysfunction in rats. 1924 2

Recent evidence suggests that mineralocorticoid receptor (MR) antagonism has beneficial effects on tissue oxidative stress and insulin metabolic signaling as well as reducing proteinuria. However, the mechanisms by which MR antagonism corrects both renin-angiotensin-aldosterone system (RAAS) impairments in renal insulin metabolic signaling and filtration barrier/podocyte injury remain unknown. To explore this potential beneficial interactive effect of MR antagonism we used young transgenic (mRen2)27 (Ren2) rats with increased tissue RAAS activity and elevated serum aldosterone levels. Ren2 and age-matched Sprague-Dawley (SD) control rats (age 6-7 wk) were implanted with a low dose of the MR antagonist spironolactone (0.24 mg/day) or vehicle, both delivered over 21 days. Albuminuria, podocyte-specific proteins (synaptopodin, nephrin, and podocin), and ultrastructural analysis of the glomerular filtration barrier were measured in relation to RAAS activation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, reactive oxygen species (ROS), and the redox-sensitive Rho kinase (ROK). Insulin metabolic signaling was determined via measurement of insulin receptor substrate-1 (IRS-1) phosphorylation, IRS-1 ubiquitin/proteasomal degradation, and phosphorylation of Akt. Ren2 rats exhibited albuminuria, loss of podocyte-specific proteins, and podocyte foot process effacement contemporaneous with reduced renal IRS-1 and protein kinase B/Akt phosphorylation compared with SD control rats (each P < 0.05). Ren2 kidneys also manifested increased NADPH oxidase/ROS/ROK in conjunction with enhanced renal tissue levels of angiotensin II (ANG II), ANG-(1-12), and angiotensin type 1 receptor. Low-dose spironolactone treatment reduced albuminuria and tissue RAAS activity and improved podocyte structural and protein integrity with improvements in IRS-1/Akt phosphorylation. Thus, in this model of RAAS activation, MR antagonism attenuates glomerular/podocyte remodeling and albuminuria, in part through reductions in redox-mediated impairment of insulin metabolic signaling.
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PMID:Mineralocorticoid receptor antagonism attenuates glomerular filtration barrier remodeling in the transgenic Ren2 rat. 1926 39

Eplerenone is an aldosterone receptor antagonist indicated for the treatment of hypertension and congestive heart failure. Eplerenone contains an epoxy group, which offers greater mineralocorticoid receptor specificity. It is an effective antihypertensive that has been shown to reduce morbidity and mortality in individuals with left ventricular dysfunction post myocardial infarction. Studies are continuing to determine whether the benefit of mineralocorticoid receptor blockade in advanced congestive heart failure is also observed when eplerenone treatment is initiated in earlier stages of the disease. The most common side effect is hyperkalemia necessitating close monitoring in individuals with diabetes and proteinuria, heart failure or in those who are taking moderate CYP450 3A4 inhibitors. It is category B in pregnancy.
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PMID:The clinical pharmacology of eplerenone. 1937 27

Obesity hypertension and metabolic syndrome have become major public health concerns. Nowadays, aldosterone is recognized as an important mediator of cardiovascular and renal damage. In the kidney, aldosterone injures glomerular visceral epithelial cells (podocytes), the final filtration barrier to plasma macromolecules, leading to proteinuria and glomerulosclerosis. Mineralocorticoid receptor (MR) antagonists effectively ameliorate proteinuria in patients or in animal models of hypertension, diabetes mellitus and chronic kidney disease (CKD), as well as in patients who experience 'aldosterone breakthrough.' Recently, clinical and experimental studies have shown that plasma aldosterone concentration is associated with obesity hypertension and metabolic syndrome. We showed that spontaneously hypertensive rats (SHR)/cp, an experimental model of obesity hypertension and metabolic syndrome, are prone to glomerular podocyte injury, proteinuria and left ventricular diastolic dysfunction, especially when the animals are fed a high-salt diet. Inappropriate activation of the aldosterone/MR system underlies the renal and cardiac injuries. Adipocyte-derived aldosterone-releasing factors (ARFs), although still unidentified, may account for aldosterone excess and the resultant target organ complication in SHR/cp. On the other hand, recent studies have shown that MR activation triggers target organ disease even in normal or low aldosterone states. We identified a small GTP (guanosine triphosphate)-binding protein, Rac1, as a novel activator of MR, and showed that this ligand-independent MR activation by Rac1 contributes to the nephropathy of several CKD models. We expect that ARFs and Rac1 can be novel therapeutic targets for metabolic syndrome and CKD. Future large-scale clinical trials are awaited to prove the efficacy of MR blockade in patients with obesity hypertension and metabolic syndrome.
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PMID:Mineralocorticoid receptor activation in obesity hypertension. 1952 18

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.
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PMID:Mineralocorticoid receptor blockade and calcium channel blockade have different renoprotective effects on glomerular and interstitial injury in rats. 1953 72

A patient with chronic kidney disease (CKD) due to membranous nephropathy with daily urinary protein excretion exceeding 5 g did not respond well to dual therapy with an angiotensin converting enzyme inhibitor (ACE-I) and angiotensin II receptor blocker (ARB). Addition of the mineralocorticoid receptor blocker (MRB), spironolactone, led to moderate reduction in daily urinary protein excretion. However, spironolactone had to be inevitably discontinued due to gynecomastia. Replacement of spironolactone with the selective MRB, eplerenone, added to the preceding treatment with ACE-I and ARB, resulted in remarkable reduction of daily urinary protein excretion to less than 0.2 g. This case suggests that triple blockade of renin-angiotensin-aldosterone (RAA) system with ACE-I, ARB, and MRB could be useful for CKD patients with massive proteinuria.
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PMID:Successful effect of triple blockade of renin-angiotensin-aldosterone system on massive proteinuria in a patient with chronic kidney disease. 1962 23

The renin-angiotensin-aldosterone system (RAAS), an important regulator of blood pressure as well as fluid and electrolyte balance, plays an important role in the pathophysiology of cardiovascular and kidney diseases. Blockade of the RAAS with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-II (ANG-II) receptor blockers (ARBs) lowers blood pressure, decreases morbidity and mortality in patients with chronic heart failure, and decreases proteinuria and the rate of decline in renal function in patients with chronic kidney disease. Although these drugs are highly effective and are widely used in the management of cardiovascular and kidney diseases, current treatment regimens with ACEIs and ARBs may not completely suppress the RAAS. Combinations of ACEIs and ARBs have been shown to be superior to either agent alone for some, but certainly not all, composite cardiovascular and kidney outcomes. With the growing appreciation of the role of aldosterone in the pathogenesis of cardiorenal diseases and the recent approval of the direct renin inhibitor (DRI), aliskiren, additional combination strategies have emerged that may offer novel ways to more fully suppress the RAAS. This review examines what is presently known about ACEI/ARB combination therapy and explores alternative combination strategies that include DRIs and mineralocorticoid receptor blockers (MRBs).
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PMID:Dual blockade of the renin-angiotensin-aldosterone system: beyond the ACE inhibitor and angiotensin-II receptor blocker combination. 1966 25

Previous studies have shown that mineralocorticoid receptor (MCR) blocker reduces proteinuria in diabetic nephropathy (DN), but the role of aldosterone in podocyte injury has never been explored in DN. This study was undertaken to elucidate whether a local aldosterone system existed in podocytes and to examine its role in podocyte apoptosis under diabetic conditions. In vitro, immortalized podocytes were exposed to 5.6 mM glucose (NG), NG + 24.4 mM mannitol, and 30 mM glucose (HG) with or without 10(-7) M spironolactone (SPR). In vivo, 32 Sprague-Dawley rats were injected with diluent (C, n = 16) or streptozotocin intraperitoneally [diabetes mellitus (DM), n = 16], and 8 rats from each group were treated with SPR for 3 mo. Aldosterone synthase (CYP11B2) and MCR mRNA and protein expression were determined by real-time PCR and Western blot, respectively, and aldosterone levels by radioimmunoassay. Western blot for apoptosis-related molecules, Hoechst 33342 staining, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay were performed to determine apoptosis. CYP11B2 and MCR expression were significantly higher in HG-stimulated podocytes and DM glomeruli compared with NG cells and C glomeruli, respectively, along with increased aldosterone levels. Western blot analysis revealed that cleaved caspase-3 and Bax expression was significantly increased, whereas Bcl-2 expression was significantly decreased in HG-stimulated podocytes and in DM glomeruli. Apoptosis determined by Hoechst 33342 staining and TUNEL assay were also significantly increased in podocytes under diabetic conditions. These changes in the expression of apoptosis-related proteins and the increase in apoptotic cells were inhibited by SPR treatment. These findings suggest that a local aldosterone system is activated and is involved in podocyte apoptosis under diabetic conditions.
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PMID:Activation of local aldosterone system within podocytes is involved in apoptosis under diabetic conditions. 1971 Feb 42

The increasing prevalence of chronic kidney disease (CKD) and the public health initiatives for detection and slowing its progression have placed special emphasis on controlling proteinuria and the renin-angiotensin-aldosterone system (RAAS). In addition to the traditional blockers of angiotensin-converting enzyme and angiotensin receptors, mineralocorticoid receptor blockers (MRBs) have come into focus as anti-proteinuric agents with moderate anti-hypertensive effects. The beneficial effects of MRBs on mortality in patients with cardiac disease have been well described. We review the role of aldosterone in end-organ damage, the rationales for using MRBs as adjuncts to angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in treating CKD, and the adverse effects that may occur when these agents are used in combination. Suggestions are included for avoiding serious adverse events in CKD patients treated with MRBs. There is a clearly defined need for prospective outcome studies focused on cardiovascular mortality as well as progression of CKD in patients treated with MRBS and other inhibitors of the RAAS.
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PMID:Mineralocorticoid receptor blockers and chronic kidney disease. 1972 30


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