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Query: UMLS:C0011881 (diabetic nephropathy)
 10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Outcome studies in diabetic nephropathy have focused on strategies to prevent progression of diabetic nephropathy, the leading cause of ESRD in the United States. Once diabetics develop overt nephropathy, prognosis is poor. Risk factors for diabetic nephropathy are discussed, and include hyperglycemia, hypertension, angiotensin II, proteinuria, dyslipidemia, smoking, and anemia. Major outcomes as well as outcome studies in diabetic nephropathy for patients with microalbuminuria and macroalbuminuria are reviewed. Furthermore, the role of therapy with angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, and mineralocorticoid receptor antagonists as well as selected combination therapy are discussed. Recommendations for therapy with ace inhibitors and angiotensin II receptor blockers are made based on this evidence.
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PMID:Outcome studies in diabetic nephropathy. 1283 94

Cells in the cortical collecting duct of distal nephron have been considered for a long time as the unique cellular targets of aldosterone. However, it is now clear that other cell types in non-epithelial tissues are also potential targets for aldosterone. The functions that this hormone controls in non-epithelial tissues are still a matter of debate. Clinical and experimental studies have established that aldosterone plays a major role in the pathophysiology of cardiovascular and renal diseases. The aldosterone receptor antagonists spironolactone and eplerenone have demonstrated specific effects not related to their hypotensive properties in hypertension or cardiac diseases. It appears that a key action of these molecules is related to prevention or treatment of end-organ damage. The latter fact, and the recognition of aldosterone escape on long-term treatment of heart failure, diabetic nephropathy and some forms of hypertension with ACE inhibitors, justify the clinical use of aldosterone receptor antagonists provided that kaliemia is controlled. Experimental studies have allowed to draw a still incomplete but comprehensive scheme of aldosterone cardiovascular actions in pathological conditions. When elevated, aldosterone has deleterious effects in blood vessels, in the heart and in kidney, which are secondary to the induction of inflammatory and oxidative processes and necrosis, that induce the increased synthesis of extracellular matrix proteins.
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PMID:Aldosterone and anti-aldosterone effects in cardiovascular diseases and diabetic nephropathy. 1552 73

We have recently shown that mineralocorticoid receptor blockade may represent optimal therapy for patients with early diabetic nephropathy who show aldosterone breakthrough during angiotensin-converting enzyme (ACE) inhibitor treatment, and who no longer show the maximal antiproteinuric effects of ACE inhibition. In this study, we explored the effects of the mineralocorticoid receptor antagonist spironolactone on urinary protein excretion in patients with chronic renal disease with proteinuria persistently more than 0.5 g/d, despite maintained blood pressure (BP) control, and including the use of an ACE inhibitor (trandolapril) for at least 10 months. After a 12-week study period of spironolactone treatment (25 mg/d), BP did not change but urinary protein excretion was significantly reduced. The extent of the reduction was on average significantly greater in diabetic patients than in nondiabetics. In patients with diabetic nephropathy, although urinary type IV collagen did not decrease after conventional treatment, it was significantly reduced by spironolactone. None of the patients developed serious hyperkalemia, and no other adverse events were observed. All patients in this study had relatively well preserved renal function. In conclusion, the present study demonstrates that in patients with chronic renal disease with proteinuria persistently more than 0.5 g/d, despite BP control and the use of an ACE inhibitor, adding spironolactone to the conventional treatment produces beneficial effects on urinary protein excretion, particularly in patients with diabetes. Our study suggests that attenuation of mineralocorticoid receptor-mediated effects may become a new goal for patients who escape the antiproteinuric effects of the conventional treatment. Additional, larger, prospective, randomized double-blind studies will be needed for general acceptance of this strategy.
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PMID:Antiproteinuric effects of mineralocorticoid receptor blockade in patients with chronic renal disease. 1569 16

Antihypertensive medications belong to different pharmacological classes. Besides blood pressure lowering properties, many substances, particularly ACE inhibitors and AT1-receptor antagonists but also in part calcium antagonists and aldosterone receptor antagonists, exert additional anti-inflammatory and antifibrotic effects as well as protective effects on endothelium. Delay of disease progression in chronic kidney disorders by inhibition of the renin-angiotensin system also as the result of blood pressure independent effects has been documented in clinical trials. On the other hand, in patients with essential hypertension without end-organ damage, it remains unclear whether the clinically proven blood pressure independent effects of antihypertensive agents are also clinically relevant. However, in clinical studies ACE inhibitors and AT1-receptor antagonists reduce the de novo occurrence of the diabetic metabolic state. Inhibition of the renin-angiotensin system decreases the incidence of diabetic nephropathy. This contribution presents currently available data on possible blood pressure independent effects of antihypertensive agents.
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PMID:[Blood pressure independent effects of antihypertensive agents]. 1580 Jul 76

In the last 10 years, many studies have focused on the non-classical action of aldosterone. One of the most important new aspects of aldosterone is its pathogenic role as proinflammatory and profibrotic molecules. It has been reported that aldosterone induces myocardial fibrosis and vascular inflammation through up-regulation of various proinflammatory and profibrotic cytokines. We investigated the effect of aldosterone and spironolactone, which is a non-selective mineralocorticoid receptor antagonist, on monocyte chemoattractant peptide (MCP-1) and collagen synthesis in cultured mesangial and tubular epithelial cells. In addition, to evaluate the effect of spironolactone on diabetic nephropathy, we used Otsuka Long-Evans Tokushima Fatty (OLETF) rats which are known type 2 diabetic animal models. Spironolactone treatment did not induce any significant change in blood glucose levels and blood pressure. However, spironolactone therapy significantly inhibited urinary albumin and MCP-1 excretion. Spironolactone treatment also suppressed renal mRNA expression for MCP-1, macrophage migration inhibitory factor (MIF) as well as intrarenal protein synthesis for ED-1 and MIF. Morphologically, spironolactone treatment significantly prevented glomerulosclerosis, collagen deposition and connective tissue growth factor (CTGF) expression in diabetic rats. In cultured cell experiments, aldosterone directly increased the MCP-1, collagen secretion and spironolactone treatment abolished aldosterone-induced MCP-1 and collagen synthesis. Surprisingly, aldosterone treatment did not induce any significant change in TGFbeta1 gene transcription. Finally, we found that NF-kB activity was increased after stimulation with aldosterone and spironolactone therapy inhibited their activation. In addition, prior treatment with pyrrolidine dithiocarbamate (PDTC), which is a NF-KB inhibitor, inhibited aldosterone-induced MCP-1 protein secretion. These results suggest that aldosterone blockade could play a role in preventing the progression of diabetic nephropathy via anti-inflammatory and antifibrotic mechanisms.
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PMID:Role of aldosterone in diabetic nephropathy. 1617 86

Aldosterone itself has been reported to participate in mediating renal injury, and it was confirmed that the aldosterone synthase CYP11B2 gene, protein, and aldosterone production are locally present in the kidney. To test the hypothesis that a mineralocorticoid receptor antagonist might ameliorate diabetic nephropathy and the inhibition of renal CYP11B2 expression might be associated with these renoprotective effects, spironolactone (50 mg/kg/day) was administered by gavage to uninephrectomized diabetic rats for 3 weeks. Streptozotocin (55 mg/kg, i.v.) significantly increased urinary protein excretion and collagen deposition in glomerular and tubulointerstitial areas in the kidney, which were attenuated by spironolactone treatment. RT-PCR and Western blot analysis revealed that the expression of mRNA for collagen I/IV, transforming growth factor-beta, NADPH oxidase and mineralocorticoid receptor and the mineralocorticoid receptor protein in the kidney was enhanced in the uninephrectomized diabetic rat kidney and that the overexpression of these molecules was suppressed by spironolactone. Renal angiotensin converting enzyme was activated and overexpressed in diabetic rats, and spironolactone inhibited these changes. We demonstrated that spironolactone prevented the streptozotocin-induced increase in the renal CYP11B2 mRNA content. Controlling blood glucose level with insulin also attenuated the renal expression of mRNA for CYP11B2. On the other hand, the treatment of spironolactone in the present study did not affect blood glucose level or blood pressure in uninephrectomized streptozotocin-induced diabetic rats. These results suggest that spironolactone exerted renoprotective effects in uninephrectomized streptozotocin-induced diabetic rats and inhibited local renin-angiotensin-aldosterone system, such as the ACE expression and the hyperglycemia-induced overexpression of CYP11B2, in the kidney.
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PMID:Spironolactone exhibits direct renoprotective effects and inhibits renal renin-angiotensin-aldosterone system in diabetic rats. 1858 58

The blockade of the renin-angiotensin-aldosterone system (RAAS) is helpful in the management of arterial hypertension, congestive heart failure, post-myocardial infarction and diabetic nephropathy. Such blockade can be obtained with an angiotensin converting enzyme inhibitor, a specific antagonist of angiotensin II AT1 receptors, an aldosterone receptor antagonist and/or a direct inhibitor of renin such as aliskiren. Various studies have demonstrated that a dual or even triple RAAS inhibition may offer a better cardiorenal protection, in refractory congestive heart failure and in nephropathy with proteinuria. However, in the ONTARGET study, the dual inhibition with ramipril plus telmisartan did not provide any additional benefit compared to ramipril alone in high-risk cardiovascular patients, but showed a worse tolerance profile.
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PMID:[What is the purpose of dual or triple inhibition of the renin-angiotensin-aldosterone system?]. 1881 62

Increasing evidence suggests that circulating aldosterone per se contributes directly to renal and cardiovascular diseases. We sought to evaluate the effects of a three-month treatment with 25 mg spironolactone, an aldosterone receptor antagonist, on nephron function in 20 type II diabetic patients with persistent microalbuminuria, despite at least six months' use of an ACEi or ARB (combination group), and in eleven type II diabetic patients with persistent microalbuminuria who have never used an ACEi or an ARB (spironolactone group). In the combination group, urinary protein excretion (UPE, p = 0.015), urinary albumin excretion (UAE, p = 0.010), and the urinary albumin to creatinine ratio (ACR, p = 0.007) decreased, and serum potassium (sK(+), p = 0.004) was significantly elevated. ACR (p = 0.016) decreased significantly in the spironolactone group. In 31 patients given spironolactone (all patients group), UPE (p = 0.019), UAE (p = 0.002), and ACR (p = 0.011) decreased, and serum creatinine (sCr, p = 0.025) and sK(+) (p = 0.002) were significantly elevated. Changes in albuminuria showed a positive correlation with changes in GFR (p = 0.002) and a negative correlation with changes in sCr (p = 0.007), and changes in ACR showed a negative correlation with changes in sCr (p = 0.004) in all patient groups. In our study, we observed that spironolactone, both alone and in combination with ACEi/ARB treatment, was well tolerated, and that it slowed down the progression of diabetic nephropathy with a marked antialbuminuric effect. Our results showed that the antialbuminuric effect developed by the decrease of intraglomerular pressure, particularly in patients with persistent microalbuminuria despite long-term ACEi/ARB treatment; adding aldosterone blockers to treatment was beneficial.
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PMID:The effects of spironolactone on nephron function in patients with diabetic nephropathy. 1901 50

Our understanding of the effects of aldosterone and its mechanisms has increased substantially in recent years, probably because of the importance of the mineralocorticoid receptor (MR) antagonists in several major cardiovascular diseases. Recent clinical studies have confirmed the benefits of MR antagonists in patients with heart failure, left ventricular dysfunction after myocardial infarction, hypertension or diabetic nephropathy. However, it would be a gross oversimplification to conclude that the role of aldosterone is unequivocally negative. Aldosterone is synthesized in the adrenal glands and binds to specific MRs in target epithelial cells. The steroid-receptor complex penetrates the cell nucleus where it modulates gene expression and activates specific aldosterone-induced proteins that control sodium reabsorption. Recent studies have shown that aldosterone also impacts a wide range of non-epithelial tissues such as the heart and blood vessels. Remarkably, aldosterone can also be synthesized in extra-adrenal tissues and it may act in a rapid non-genomic manner.We note the existence of glucocorticoids that exhibit plasma concentrations much higher than those of aldosterone and that are structurally very similar to aldosterone. It is thus possible that glucocorticoids may bind to the aldosterone receptor in some cell types. Diverse experimental models and several strains of transgenic mice have allowed us to better understand the effects of aldosterone on the heart. Specifically, it seems that a slight increase in cardiac aldosterone concentrations induces a decreased coronary reserve in mice by decreasing the BKCa potassium channels associated with coronary smooth muscle cells. Taken together, these experiments indicate that vascular cells are the primary targets of aldosterone in the cardiovascular system. The hormone directly affects NO and EDHF-mediated coronary relaxation. Both mechanisms may contribute to the deleterious cardiovascular effects of MR stimulation.
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PMID:Effects of aldosterone on coronary function. 1930 93

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


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