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)

Serum and lung angiotensin-converting enzyme (ACE) activity is increased in the streptozotocin (STZ)-diabetic rat. In the present study, the effect of insulin treatment on this increased ACE activity in the STZ-diabetic rat was investigated. Serum and tissue ACE activity was determined by radiometric assay using [3H]-Hippuryl-glycyl-glycine as substrate. Fifteen days after onset of diabetes (n = 16), 8 rats received insulin daily (6-12 units/kg, s.c.) for 33 days, 8 diabetes rats remained untreated. Control, non-diabetic, rats (n = 8) received saline. The baseline serum ACE activity in the control group was 595 +/- 13 nmol/ml/min and did not change significantly throughout the study. However, serum ACE activity in the untreated diabetic rats increased significantly as of day 14 post-STZ (650 +/- 24 nmol/ml/min, p < 0.001) compared to the corresponding values of the control group and compared to baseline values. Insulin administration to diabetic rats starting on day 15 post-STZ caused a gradual reduction in serum ACE activity to basal values, being (527 +/- 22 nmol/ml/min) at day 47. ACE activity in lungs of untreated diabetic rats was increased by 46%, 47 days post-STZ. Insulin treatment reduced lung ACE activity to values similar to those observed in non-diabetic rats. These changes were associated with reduced kidney weight and urine volume. In summary, insulin administration to hyperglycaemic rats resulted in a reduction in the enhanced serum and lung ACE activity to values seen in non-diabetic rats. Normalizing the activity of the renin-angiotensin system may slow or prevent the glomerular hypertension, a major factor in the development of diabetic nephropathy.
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PMID:Insulin treatment reduces the increased serum and lung angiotensin converting enzyme activity in streptozotocin-induced diabetic rats. 951 60

Transforming growth factor-beta (TGF-beta) and the renin-angiotensin system (RAS) have both been implicated in the pathogenesis of glomerulosclerosis in diabetic kidney disease. However, tubulointerstitial pathology may also be an important determinant of progressive renal dysfunction in diabetic nephropathy. In the present study, we investigated tubulointerstitial injury, TGF-beta1 expression, and the effect of blocking the RAS by inhibition of ACE. We randomized 36 male SD rats to control and diabetic groups. Diabetes was induced in 24 rats by administration of streptozotocin; 12 diabetic rats were further randomized to receive the ACE inhibitor ramipril (3 mg/l drinking water). At 6 months, experimental diabetes was associated with tubulointerstitial damage, a 70% increase in expression of TGF-beta1 (P < 0.05 vs. control), and a 120% increase in alpha1 (IV) collagen gene expression (P < 0.01 vs. control). In situ hybridization demonstrated a diffuse increase in both TGF-beta1 and alpha1 (IV) collagen mRNA in renal tubules. In addition, intense expression of both transcripts was noted in regions of focal tubular dilatation. Administration of the ACE inhibitor ramipril prevented tubulointerstitial injury and the overexpression of TGF-beta1 and alpha1 (IV) collagen mRNA. Changes in gene expression were accompanied by parallel changes in immunostaining for TGF-beta1 and type IV collagen. The observed beneficial effects of ramipril on the tubulointerstitium in experimental diabetes suggest that this mechanism may contribute to the therapeutic effect of ACE inhibitors in diabetic nephropathy.
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PMID:Expression of transforming growth factor-beta1 and type IV collagen in the renal tubulointerstitium in experimental diabetes: effects of ACE inhibition. 951 48

Diabetic nephropathy (DN) clusters in families with type 1 diabetes and the degree of clustering suggests that a major gene having a common disease allele may be responsible. To investigate the chromosomal regions containing genes for the renin-angiotensin system, we performed a linkage study using pairs of siblings with type 1 diabetes who were discordant for DN. Theoretical considerations supported by simulation studies indicated that such discordant pairs, rather than the usual concordant pairs, would be more effective in detecting a major susceptibility gene for DN. We applied this novel strategy to test for linkage between DN and chromosomal regions containing genes for the ACE, angiotensinogen (AGT), and angiotensin II type 1 receptor (AT1). Two polymorphic markers were genotyped in the vicinity of each of the three loci in 66 discordant sib pairs and were analyzed with multipoint methods. The regions containing ACE and AGT loci were not linked with DN, while the region containing the AT1 locus showed linkage with DN. As a result of these positive findings, eight additional polymorphic markers spanning a 63-cM region around AT1 locus were genotyped. Linkage was demonstrated between DN and a 20-cM region that includes AT1 (P = 7.7 x 10(-5)), an obvious candidate gene for DN. To investigate whether AT1 could account for the observed linkage, we sequenced all exons, splicing junctions, and the promoter region and examined the identified polymorphisms/mutations for association with DN using the transmission disequilibrium test. Four new polymorphisms in the gene were found, but neither these nor previously described polymorphisms were associated with DN. Thus, while our study does not implicate AT1 itself in the etiology of DN, it provides very strong evidence that a 20-cM region around AT1 contains a major locus for susceptibility to DN.
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PMID:Major susceptibility locus for nephropathy in type 1 diabetes on chromosome 3q: results of novel discordant sib-pair analysis. 964 45

The renin-angiotensin system is central to the pathophysiology of a number of cardiovascular disorders. Most obviously this is so with renin secreting tumours, but the system is of central importance in other disorders such as scleroderma renal crisis and most cases of malignant hypertension. Activation of the renin-angiotensin system in unilateral renal artery stenosis is pivotal to the development of hypertension and the disturbances in electrolyte and volume balance -- most particularly in the hyponatraemic-hypertensive syndrome. Likewise, stimulation of the renin-angiotensin system is an important contributor, amongst many other systems, to the pathophysiology of cardiac failure. In diabetic nephropathy, the renin-angiotensin system is often suppressed as gauged by circulating levels of renin, yet it appears to make an important contribution to the progressive decline in renal function. Much less clear is the role of the renin-angiotensin system in essential hypertension insofar as it contributes to the level of blood pressure, to the development of left ventricular hypertrophy, and in the evolution of complications such as stroke and myocardial infarction. Blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors has contributed to our understanding of the role of this system in cardiovascular disease. The advent of selective angiotensin II type-1 receptor blockers will further increase knowledge in this area.
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PMID:The importance of the renin-angiotensin system in cardiovascular disease. 965 50

The effect of exposure to diabetes on the kidney appears to be modulated by genetic factors determining a variable degree of susceptibility to diabetic nephropathy. Multiple loci are probably involved. Some of them might be found among the genes coding for components of the renin angiotensin system (renin, angiotensinogen, angiotensin I-converting enzyme, angiotensin receptors), some may regulate the way in which cells manage hyperglycemia (e.g. aldose reductase). Various genes have been examined to date, mainly by means of association studies. Positive results have been found for some of them (e.g. ACE, AGTR1, aldose reductase), but have not been confirmed in other populations. Thus, no genetic marker of increased susceptibility to diabetic nephropathy having clinical utility is currently available. New insights are expected from the systematic scanning of the genome for linkage with diabetic nephropathy.
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PMID:Genetic markers of increased susceptibility to diabetic nephropathy. 967 90

It is likely that the pathophysiology of diabetic nephropathy involves an interaction of metabolic and haemodynamic factors. Relevant metabolic factors include glucose-dependent pathways such as advanced glycation, increased formation of polyols, and activation of the enzyme, protein kinase C. Specific inhibitors of the various pathways are now available, enabling investigation of the role of these processes in the pathogenesis of diabetic nephropathy and potentially to provide new therapeutic approaches for the prevention and treatment of diabetic nephropathy. Haemodynamic factors to consider include systemic hypertension, intraglomerular hypertension, and the role of vasoactive hormones, such as angiotensin II. The mainstay of therapy remains attaining optimum glycaemic control. Antihypertensive therapy has a major role in slowing the progression of diabetic nephropathy. Agents that interrupt the renin-angiotensin system such as angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists may be particularly useful as renoprotective agents in both the hypertensive and normotensive context.
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PMID:Pathogenesis, prevention, and treatment of diabetic nephropathy. 968 26

Poor metabolic control, hemodynamic factors and long duration of diabetes may predispose to the development of diabetic nephropathy. Recently the hypothesis that genetic factors may play certain role in the pathogenesis of diabetic nephropathy has been also proposed. The angiotensin I converting enzyme (ACE) gene has been the main candidate gene predisposing to the development of diabetic nephropathy. One of its polymorphisms--insertion/deletion seems to be particularly associated with long-term diabetic complications. There are many candidate genes taking probable part in the pathogenesis of diabetic nephropathy. Among them we must think about: the HLA system genes, cations transporters genes, renin-angiotensin system genes, insulin sensibility dependent genes, genes coding basement membrane, genes taking part in apoprotein synthesis regulation. If there would be strong evidence that genetic factors play certain role in the pathogenesis and progression of diabetic nephropathy, the high risk diabetics could be selected and the adequate prevention could be applied.
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PMID:[The significance of candidate genes' polymorphism in the development of diabetic nephropathy]. 968 28

An increase in glomerular filtration rate (GFR) in early diabetes mellitus is considered a risk factor for the development of diabetic nephropathy. Insulin deficiency may increase the activity of ATP-sensitive potassium channels (KATP), which could promote afferent arteriolar vasodilation und thus contribute to glomerular hyperfiltration in early diabetes mellitus. To further elucidate this hypothesis we performed renal clearance experiments in anesthetized rats at 2 and 6 weeks after onset of streptozotocin-induced insulin-treated diabetes mellitus and studied the acute effect of the putative KATP channel blocker 4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexylhydr ochloride (U37883A) on renal function. In control rats, application of U37883A (1.5 mg/kg i.v. bolus plus 1.5 mg/kg/hr) induced a significant reduction in heart rate, but did not affect or even slightly increased mean arterial blood pressure. Furthermore, U37883A did not significantly affect renal vascular resistance, renal blood flow or GFR, but caused an eukaliuretic diuresis and natriuresis and lowered plasma renin activity. Diabetic rats at both 2 or 6 weeks after streptozotocin exhibited essentially an identical response to U37883A; in particular, RVR and glomerular hyperfiltration remained unchanged. These results show that in both control and diabetic rats, the renal excretory function, renin secretion and pace setting in the heart were sensitiv to U37883A, implying a functional contribution of KATP channel activity. However, in both control and diabetic rats, renal vascular resistance, renal blood flow, or GFR were not altered by U37883A. These results argue against a substantial role for KATP channels in the basal control of renal hemodynamics in both nondiabetic and diabetic rats.
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PMID:Effect of KATP channel blocker U37883A on renal function in experimental diabetes mellitus in rats. 973 81

Increasing worldwide rates of diabetes mellitus, combined with the significant micro- and macrovascular complications that accompany the disease, point to a heightened need to develop simple, rational strategies to protect against end-organ damage, particularly diabetic nephropathy. Although simple strategies do exist, i.e., early diagnosis of microalbuminuria (MAU) followed by nephroprotective therapy with angiotensin-converting enzyme (ACE) inhibitors, the use of these techniques should be increased. This is especially true for primary care physicians, who will continue to handle the majority of diabetic patients. To combat the underuse of this dual approach, this article reviews a stepwise approach to identifying early MAU so that therapeutic measures can be undertaken before the disorder progresses to diabetic nephropathy and, consequently, to end-stage renal disease in the majority of patients. Once a diagnosis of MAU is made, a variety of trials have demonstrated that ACE inhibitor therapy should be considered the standard therapy to retard worsening albuminuria and subsequent renal disease. ACE inhibitors can retard the progression of microalbuminuria and can lower the percentage of patients who progress to end-stage renal disease and death. Significant data indicate that ACE inhibitors should be used in MAU diabetics regardless of the level of blood pressure. In particular, the ACE inhibitor fosinopril may offer advantages because of its dual route of elimination, thus simplifying dosing in renally impaired patients. The newly developed angiotensin II receptor antagonists should be considered in patients intolerant to ACE inhibitors because of the similar effect on the interruption of the renin-angiotensin system.
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PMID:Relationships among diabetes, microalbuminuria, and ACE inhibition. 973 36

Blockade of the renin-angiotensin system with angiotensin-converting enzyme (ACE) inhibitors is now recognized as an effective approach for the treatment of hypertension and congestive heart failure. In addition, ACE inhibitors are very effective for the prevention of chronic renal failure. Today, it is possible to antagonize the effects of angiotensin II more specifically using AT1 receptor antagonists. Several non-peptide, orally active angiotensin II receptor antagonists have recently been developed clinically. These new molecules are as effective as ACE inhibitors, calcium antagonists and beta-blockers at reducing blood pressure in hypertensive patients. Furthermore, they appear to have similar systemic and renal hemodynamic properties in patients with congestive heart failure and renal diseases. Now, several large clinical trials such as the LIFE, the RENAAL and the ELITE II studies are under way to investigate the long-term benefits of one of these compounds in hypertension, heart failure and type II diabetic nephropathy.
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PMID:[Angiotensin II AT1 receptor antagonists: clinical development and future perspectives]. 977 27


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