Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011881 (diabetic nephropathy)
 10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The kidney plays an important role in protein metabolism. The albumin reabsorption in the proximal tubule is disturbed in the early stage of diabetic nephropathy. We evaluated the effects of angiotensin converting enzyme inhibitor (ACEI) and angiotensin III type 1 receptor blocker (ARB) on albumin reabsorption and expression of megalin, an endocytosis receptor for albumin, in proximal tubules of streptozotocin (STZ)-induced diabetic-rats. Diabetic rats at the second week after STZ injection were treated with quinapril (3 mg/kg/day) or candesartan (0.05 mg/kg/day) for 2 weeks. The tubular reabsorption of fluorescein isothiocyanate (FITC)-labeled albumin was evaluated by immunogold electron microscopy, and megalin expression was investigated by immunohistochemistry and Western blotting. Reabsorption of FITC-labeled albumin and megalin expression were prominently inhibited in the proximal convoluted tubules of diabetic rats compared to the controls. Both quinapril and candesartan restored albumin reabsorption in the proximal tubule due to normalization of megalin expression. Urinary albumin excretion was significantly reduced by both ACEI and ARB treatment. Angiotensin II infusion decreased megalin expression and albumin reabsorption in the proximal tubule. In conclusion, angiotensin II blockade restored albumin reabsorption via amelioration of megalin expression in the proximal tubules of early stage diabetic rats.
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PMID:Angiotensin II blockade restores albumin reabsorption in the proximal tubules of diabetic rats. 1288 33

Diabetic nephropathy (DN) is the most common cause of chronic renal failure (CRF), in Mexico prevalence of diabetes is higher than other countries. Genetic susceptibility, arterial hypertension, proteinuria and initial hyperfiltration are risk factors for CRF. Renal injury is mediated by protein glycation, proteinuria and hemodynamics alterations induced by arterial hypertension and impaired renal autoregulation. Angiotensin II is directly involved in renal injury through its hemodynamic effects, oxidative stress, induction of proinflammatory and profibrotic factors and cellular proliferative effect. Prospective, well controlled clinical trials in patients with type 1 and type 2 DM have shown that interrupting the renin angiotensin system with CEI or ARA effectively prevent progression of DN. Combination of both drugs may provide further nephroprotection. Antihypertensive therapy in patients with DN must include CEI or ARA and to reduce BP below 130/85 mmHg and if proteinuria is present, under 120/75.
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PMID:[Arterial hypertension and diabetic nephropathy. Evidence based therapy]. 1296 48

During the past decade, the incidence of end-stage renal disease (ESRD) has risen dramatically, primarily due to an increase in the incidence of diabetes. In patients with diabetes, both hyperglycemia and hypertension are independent risk factors for renal disease. Hypertension is also a risk factor in nondiabetic renal disease and contributes to renal dysfunction by increasing glomerular pressure, glomerular capillary damage, and proteinuria. The resultant nephron damage increases glomerular pressure and damage within remnant functional nephrons, further contributing to deterioration of renal function. In addition to its role in systemic hypertension, angiotensin II has direct effects on the kidney through elevation of glomerular capillary pressure and upregulation of components of the renal injury response. These direct effects of angiotensin II on the kidney support the inclusion of agents that target the renin-angiotensin system (RAS) into treatment regimens for patients at risk for renal disease. Several clinical trials have established the benefits of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in patients with diabetes. The ACE inhibitors have been shown to delay renal decline in patients with type 1 diabetes, whereas the renoprotective effect of these agents in patients with type 2 diabetes is less clear. The ARBs have been shown to provide significant benefits in patients with type 2 diabetes, both at early (microalbuminuria) and late (proteinuria) stages of renal decline. In the Irbesartan Diabetic Nephropathy Trial (IDNT) and the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study, ARB therapy significantly reduced the progression of overt nephropathy (composite of doubling of serum creatinine, ESRD, and death), a benefit that has not been shown for ACE inhibitors. Moreover, in RENAAL, losartan significantly reduced the incidence of the individual end point of ESRD. The benefits of ARB therapy in IDNT and RENAAL were associated with significant reductions in proteinuria and were independent of blood pressure reductions. In RENAAL, proteinuria was a strong predictor of both renal and cardiovascular events. These findings underscore the importance of RAS blockade as a strategy for improving clinical outcomes in patients with renal disease.
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PMID:Recommendations for the management of special populations: renal disease in diabetes. 1462 61

Olmesartan is an angiotensin II receptor antagonist indicated for the treatment of essential hypertension. Angiotensin II is an important hormonal effector and end-product of the renin-angiotensin system. When it binds to its endogenous receptor sites, it causes widespread vasoconstriction and a subsequent increase in blood pressure. Olmesartan works by selectively binding to AT(1) against the pathophysiologic events leading to diabetic nephropathy and cardiovascular morbidity/mortality. This end-organ protection is independent of olmesartan's blood pressure lowering properties and is therefore thought to be mediated by different mechanisms. In summary, olmesartan has an efficacy profile superior to other available antihypertensive agents, with a tolerability profile comparable to that of placebo. In addition, the convenience of its once-daily dosing means that olmesartan should be considered not only as an alternative, but also as a first-line treatment for patients with mild to severe essential hypertension. Thus, olmesartan appears to be a very promising new therapy for the treatment of hypertension.
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PMID:Olmesartan, an AT1-selective antihypertensive agent. 1466 30

The development of drugs which block the renin-angiotensin system (RAS) has been proven a major advance in cardiovascular medicine. Angiotensin converting enzyme (ACE) inhibitors, which block the formation of angiotensin II from the inactive angiotensin I, are widely used as first line treatment in hypertension, heart failure and diabetic nephropathy. More recently, selective antagonists of the angiotensin type-1 receptor (AT1R) have become available for clinical use. Accumulating evidence suggests that AT1R antagonists have similar effects to ACE inhibitors in hypertension, heart failure and diabetic nephropathy. Although ACE inhibitors and AT1R antagonists block the same system, experimental evidence suggest that their mechanisms of action differ in several respects, such as increased bradykinin and angiotensin 1-7 levels with ACE inhibitors and AT2R activation with AT1R antagonists. Nevertheless, the clinical significance of these differences remains largely unknown and, in practice, the only clear advantage of AT1R antagonists over ACE inhibitors is the absence of cough as a side effect. Recent clinical data suggest that combined ACE inhibition and AT1R antagonism offer additive effects in reducing blood pressure in hypertension, in reducing proteinuria in nephropathy and in improving prognosis in heart failure. Further evidence suggests that some hypertensive patients may have a good antihypertensive response with ACE inhibition but not with AT1R antagonism, or the reverse. These data suggest that these two drug classes have important similarities, because they act on the same system, but they also appear to have important differences, which are not only of theoretical but also of clinical importance.
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PMID:Renin-angiotensin system blockade at the level of the angiotensin converting enzyme or the angiotensin type-1 receptor: similarities and differences. 1496 13

Diabetic nephropathy is the leading cause of end stage renal disease (ESRD), and given that treating this condition is a considerable economic burden, the prevention of ESRD is a major public health goal. The renin-angiotensin system (RAS) is aberrantly activated in patients with diabetes. Angiotensin II (AII), a downstream effector of the RAS, has haemodynamic and non-haemodynamic effects that contribute to the development and progression of nephropathy. For patients with type 2 diabetes mellitus (T2DM) and hypertension, an AII receptor blocker (AIIRB) is recommended as the first drug that should be used. This review will focus on the rationale for the use of losartan as a treatment for nephropathy associated with T2DM. In animal models of diabetes, losartan reduced proteinuria and conferred renal protection. In RENAAL (Reduction in Endpoints in Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan), the first major randomised trial that investigated the benefit of losartan in patients with T2DM and nephropathy, losartan significantly reduced the risk of a doubling of serum creatinine and progression to ESRD, significantly lowered the levels of proteinuria and slowed the rate of decline in glomerular filtration rate. This review also discusses other clinical trials of losartan and other AIIRBs in T2DM, and considers alternative mechanisms by which losartan may be exerting its effects. The collective experience in treatment trials highlighted in this review indicate that losartan and other AIIRBs can reduce blood pressure and the progression of proteinuria in diabetic renal disease. However, losartan is thus far the only AIIRB that has been shown to reduce significantly the risk of ESRD and cardiovascular events in patients with T2DM. Its use in hypertensive patients with T2DM and nephropathy may play an important role in reducing the burden of ERSD.
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PMID:Advances in the treatment of diabetic renal disease: focus on losartan. 1502 42

VEGF expressed in glomerular podocytes, is known to increase vascular permeability to macromolecules. Angiotensin II can stimulate the release of VEGF, and the protective effects of angiotensin II antagonist against diabetic glomerular injury suggest that the angiotensin II-induced VEGF is an important pathogenetic mechanism in the development of proteinuria during diabetic nephropathy although this mechanism is not fully understood. In this study, the changes of VEGF expression was examined in the experimental diabetic nephropathy to determine whether these changes were modified by renoprotective intervention by blockers of angiotensin II receptors. The streptozotocin- induced diabetic rats were treated with L-158,809, a blocker of angiotensin II receptors, for 12 weeks. Age-matched rats with L-158,809 served as controls. RT-PCR and immunohistochemistry were used to assess and quantify gene and protein expression of VEGF. A progressive increase in urinary protein excretion was observed in diabetic rats. Glomerular VEGF expression was significantly higher in diabetic rats than in the control groups, with a significant reduction in glomerular VEGF expression and proteinuria in L-158,809- treated diabetic rats. VEGF mRNA was also significantly higher in diabetic kidneys than in the control groups, with a significant reduction in VEGF mRNA in L-158,809-treated diabetic kidneys. These results demonstrates that VEGF expression is significantly increased in diabetic podocytes, and angiotensin II receptor antagonist attenuated these changes in VEGF expression and prevented the development of proteinuria in vivo. Attenuation of increased VEGF expression in podocytes could contribute to the renoprotective effects of angiotensin II receptor antagonists in diabetic nephropathy.
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PMID:Angiotensin II receptor blocker attenuates overexpression of vascular endothelial growth factor in diabetic podocytes. 1503 73

Diabetic nephropathy has become the single most important cause of end-stage renal disease in the USA, Europe and Japan. The earliest marker of incipient diabetic nephropathy is the transition of normoalbuminuria to microalbuminuria at an albumin excretion rate of 20 microg/min. Human studies in patients both with and without diabetic kidney diseases have shown that the severity of baseline proteinuria is an important predictor of the rate of loss of renal function. Moreover, the reduction in protein excretion rate when patients with nephropathies are being treated with antihypertensive agents predicts the efficacy of subsequent renoprotection. Experimental and clinical observations provide the rationale for targeting the renin-angiotensin system as a renoprotective approach in diabetic and nondiabetic proteinuric nephropathies. Losartan (Cozaar, Merck Sharpe and Dohme) is a potent, orally active and highly specific angiotensin-type 1 receptor blocker. In addition to its antihypertensive efficacy, losartan decreases the left ventricular mass index in patients with hypertension, left ventricular end-diastolic and end-systolic volume in subjects with heart failure and prevents cardiovascular morbidity and death, predominantly stroke, independent of blood pressure reduction. Short-term studies in Type 1 diabetic patients with overt nephropathy have demonstrated that losartan and angiotensin-converting enzyme inhibitors have similar beneficial effects on albumin excretion rate, blood pressure and renal hemodynamics. Losartan also lowered albumin excretion rate in microalbuminuric patients with Type 2 diabetes mellitus. Moreover, the large multicenter Reduction of End points in Noninsulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL) trial has shown that blockade of angiotensin-type 1 receptor with losartan is superior to conventional antihypertensive therapy in slowing the progression of overt Type 2 diabetic nephropathy. Together, data from clinical trials demonstrate the beneficial effect of angiotensin-type 1 receptor blockers, including losartan, in the primary and secondary prevention of renal disease progression in diabetic patients. Nevertheless, it can be expected that the positive results achieved so far with this class of drugs may be further implemented by including angiotensin-type 1 receptor antagonists as a part of the multidrug approach that may hold more promise for the future of renoprotection in diabetic patients with chronic nephropathy.
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PMID:Losartan in diabetic nephropathy. 1522 8

We found that when a site-specific binding protein interacts with the "handle" region of the prorenin prosegment, the prorenin molecule undergoes a conformational change to its enzymatically active state. This nonproteolytic activation is completely blocked by a decoy peptide with the handle region structure, which competitively binds to such a binding protein. Given increased plasma prorenin in diabetes, we examined the hypothesis that the nonproteolytic activation of prorenin plays a significant role in diabetic organ damage. Streptozotocin-induced diabetic rats were treated with subcutaneous administration of handle region peptide. Metabolic and renal histological changes and the renin-Ang system components in the plasma and kidneys were determined at 8, 16, and 24 weeks following streptozotocin treatment. Kidneys of diabetic rats contained increased Ang I and II without any changes in renin, Ang-converting enzyme, or angiotensinogen synthesis. Treatment with the handle region peptide decreased the renal content of Ang I and II, however, and completely inhibited the development of diabetic nephropathy without affecting hyperglycemia. We propose that the nonproteolytic activation of prorenin may be a significant mechanism of diabetic nephropathy. The mechanism and substances causing nonproteolytic activation of prorenin may serve as important therapeutic targets for the prevention of diabetic organ damage.
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PMID:Inhibition of diabetic nephropathy by a decoy peptide corresponding to the "handle" region for nonproteolytic activation of prorenin. 1548 60

The results issued from experimental models and randomized controlled clinical trials have shown that the more intense is the blockade of the renin-angiotensin system (RAS), the more effective is the prevention of target organ damage. Combined inhibition of the RAS is aimed at more complete blockade of the system through action at two different sites, angiotensin I converting enzyme (ACE) and AT1 receptors. This is achieved either by neutralizing the rise in renin and angiotensin (Ang) I, which follows the interruption of the Ang II-renin negative feed-back loop, or by directly antagonizing Ang II, whose synthesis is in part independent of the RAS. By comparison with higher doses of single site RAS blockers, a combination of an ACE inhibitor and an AT1 receptor antagonist block more effectively the RAS. After the demonstration of its synergistic or additive blood pressure lowering effects in sodium depleted normotensive subjects and animal models, combined blockade of the RAS was shown to be more efficient than single site RAS blockade: 1. in lowering blood pressure in hypertensive patients; 2. in lowering proteinuria and possibly retarding progression of renal failure in patients with diabetic and non-diabetic nephropathy; 3. finally, in improving left ventricular remodelling, cardiac function status and cardiovascular morbidity and mortality in patients with congestive heart failure. The advantage offered by combining two RAS blockers is to increase the beneficial effect of cardioprotection and nephroprotection which are currently demonstrated with the highest doses of an ACE inhibitor or an AT1 receptor antagonist.
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PMID:[Blockade of the renin-angiotensin system by a combination of ACE inhibitors and AT1 receptor antagonists]. 1549 22


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