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

We have previously reported that the mRNA levels of endothelin (ET-1), tumor necrosis factor-alpha), (TNF-alpha), platelet-derived growth factor (PDGF)-B chain, transforming growth factor (TGF-beta), and basic fibroblast growth factor (bFGF) all increased with age in diabetic rat glomeruli. We have now assessed the effect of the angiotensin-converting enzyme inhibitor enalapril on the expression of the ET-1, TNF-alpha, PDGF-B, TGF-beta, and bFGF genes in 24-week-old rat glomeruli after streptozotocin injection. Animals were divided into controls, enalapril-treated diabetic rats, and untreated diabetic rats. Treatment continued for 24 weeks. Enalapril reduced both creatinine clearance (p < 0.001) and urinary protein excretion (p < 0.01) in diabetic rats. Enalapril produced a nonsignificant 15 mm Hg reduction in blood pressure in diabetic rats. Enalapril also attenuated the increases in ET-1 mRNA levels observed in the glomeruli of diabetic rats (0.5-fold compared with untreated diabetic rats at 24 weeks [p < 0.01]) but had no effect on increased mRNA levels of TNF-alpha, PDGF-B, TGF-beta, and bFGF. These findings suggest that enalapril therapy may be effective in reducing ET-1 mRNA expression in the glomeruli of diabetic nephropathy.
 ...
PMID:Effects of enalapril on endothelin-1 and growth factor gene expression in diabetic rat glomeruli. 819 82

The presence of immunoreactive endothelin (IR-ET) was studied by radioimmunoassay in human kidney with and without clinical renal failure, and the levels were compared with those of three natriuretic peptides: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). Kidney tissues were obtained at autopsy from three subjects with renal disorders (diabetic nephropathy, renal tubular necrosis, and end-stage kidney disease). Normal renal tissue was obtained at surgery from two patients with renal cell carcinoma. IR-ET was detected in three diseased kidneys obtained at autopsy (0.101 +/- 0.043 pmol/g wet weight, mean +/- SD) but not in tissues of two normal kidneys obtained at surgery (< 0.015 pmol/g wet weight). Reverse-phase HPLC showed that most of the IR-ET in the kidney (> 90%) was eluted in the position of ET-1. IR-ANP (0.23 +/- 0.06 pmol/g wet weight), IR-BNP (1.15 +/- 0.94 pmol/g wet weight), and IR-CNP (0.44 +/- 0.16 pmol/g wet weight) were detected in all samples examined. Higher concentrations of IR-BNP were found in three diseased kidneys obtained at autopsy (1.70 +/- 0.83 pmol/g wet weight vs. mean in two normal kidney tissues, 0.32 pmol/g wet weight). Such increases were not observed in IR-ANP or IR-CNP. These findings indicate that IR-ET is present in the human diseased kidney even in end-stage disease, with high concentrations comparable to those of natriuretic peptides. This raises the possibility that the production of ET-1 and BNP is increased in kidneys of patients with renal disorders.
 ...
PMID:Immunoreactive endothelin in the human kidney: comparison with natriuretic peptides. 858 63

Chronic nephropathies are associated with enhanced renal synthesis of endothelin (ET)-1. A recent study demonstrated that an ET(A) receptor antagonist given to diabetic rats at the moment of disease induction prevented the development of renal injury. Here we investigated whether an unselective ET(A)/ET(B) receptor antagonist, PD 142,893, was renoprotective when given to streptozotocin diabetic rats when animals were already proteinuric. The effect of PD 142,893 was compared with that of an ACE inhibitor, lisinopril, known to retard progressive renal disease in experimental and human diabetes. PD 142,893 normalized systemic blood pressure, reduced urinary protein and albumin excretion, and ameliorated renal blood flow in diabetic rats, but it did not affect such parameters in control rats. Lisinopril had a renoprotective effect comparable to PD 142,893, although lisinopril controlled systemic blood pressure better. Northern blot analysis of ET-1 mRNA revealed upregulation of ET-1 gene in the diabetic kidney. Similar results were obtained by in situ hybridization in glomeruli and tubuli of diabetic rats. Both treatments remarkably attenuated exaggerated renal ET-1 gene expression. These data suggest that ET-1 is a contributory mediator of kidney damage in diabetes and indicate that ET receptor antagonists may represent a new therapeutic mean for treatment of progressive diabetic nephropathy.
 ...
PMID:Unselective inhibition of endothelin receptors reduces renal dysfunction in experimental diabetes. 951 53

An activated renal endothelin (ET) system is implicated in the pathogenesis of renal fibrosis, as recently shown in ET-1 transgenic mice. Because progressive renal fibrosis is also a major finding in diabetic nephropathy, we analyzed the activity of the renal ET system in rats with streptozotocin-induced diabetes mellitus and the effect of blocking the ETA receptor, using the orally active ETA antagonist LU 135252. The effects of long-term treatment with LU 135252 were compared with those of an ACE inhibitor. Plasma and urinary ET-1 concentrations were measured. Progression of diabetic nephropathy was analyzed by measuring urinary albumin and protein excretion. Urinary ET-1 excretion was significantly elevated as early as 7 days after induction of diabetes and increased further. The daily urine volume was significantly correlated with urine ET-1 excretion. Treatment with LU 135252 significantly decreased the ET-1 excretion by more than 50%, whereas ACE inhibition resulted only in a mild decrease. Albumin excretion was significantly decreased after ACE inhibition, whereas ETA inhibition resulted in a nonsignificant decrease. Urinary ET and albumin excretion probably reflect independent mechanisms of renal damage in diabetes.
 ...
PMID:Renal endothelin system in diabetes: comparison of angiotensin-converting enzyme inhibition and endothelin-A antagonism. 959 22

Endothelin (ET) is a potent vasoconstrictive peptide that may play a role in vascular pathology in general and diabetic nephropathy in particular. The aim of this study was to investigate (1) alterations of urinary ET1 (UET1) in adolescents and young adults with insulin-dependent diabetes mellitus (IDDM) and (2) the relation of UET1 to other indices of diabetic nephropathy and to risk factors of diabetic angiopathy in general. In 130 IDDM subjects aged 15.2+/-4.9 years with a diabetes duration of 7.3+/-5.1 years, UET1 by radioimmunoassay, urinary albumin by nephelometry, plasma renin by immunoradiometric assay, hemoglobin A1c (HbA1c) by high-performance liquid chromatography, and routine biochemistry analyses were determined. Forty-eight controls, healthy siblings of the diabetics of comparable age, were similarly studied. Total 24-hour UET1 excretion was higher in diabetics than in controls (10,866+/-7,270 and 6,598+/-3,294 pg/24 h, respectively, P=.000). This difference was also noted if male and female diabetics were separately compared with controls. In diabetics with normoalbuminuria (<20 microg/min), total 24-hour UET1 excretion was also higher than in controls (P=.002). In diabetics but not in controls, 24-hour UET1 values were higher in males than in females (P=.018). In IDDM subjects, UET1 showed a linear relationship with age (P=.002), urinary albumin (P=.000), serum creatinine (P=.001), systolic blood pressure (P=.038), triglycerides (P=.003), and HbA1c (P=.041). Multiple regression analysis demonstrated that the variables interacting independently with UET1 were urinary albumin (P=.003) and serum creatinine (P=.038). UET1 is elevated early (in adolescence) in IDDM subjects, and it is positively correlated with the degree of albuminuria. These data suggest that the amount of UET1 possibly reflects the severity of diabetic renovascular damage. It may thus be speculated that UET1 could be used as another index of diabetic nephropathy or its progress.
 ...
PMID:Urinary endothelin in adolescents and young adults with insulin-dependent diabetes mellitus: relation to urinary albumin, blood pressure, and other factors. 982 22

Both reactive oxygen species (ROS) and endothelin-1 (ET- 1) have been implicated in the pathophysiology of diabetic nephropathy. The interrelationship between them, however, has not been documented in this disease. To determine whether ROS regulates ET-1 production in diabetic kidneys, we examined the in vitro and in vivo effects of ROS donors and scavengers on ET-1 production of diabetic rat glomeruli. For in vitro study, the glomeruli were isolated with a sieving method from streptozotocin-induced diabetic rats and killed at 1 week, 1 month, and 3 months, respectively. Superoxide was measured by a spectrophotometer, and ET-1 was measured by radioimmunoassay. The results demonstrated that the basal production levels of superoxide and ET-1 were higher in diabetic glomeruli than in normal glomeruli in vitro. There was a positive correlation between the production of superoxide and ET-1 in diabetic glomeruli. The basal ET-1 production was markedly attenuated by ROS scavengers including superoxide dismutase, catalase, dimethyl sulfoxide, and deferoxamine in diabetic glomeruli. Exogenous ROS generated by xanthine/xanthine oxidase significantly enhanced ET-1 generation by both diabetic and normal glomeruli. A high glucose concentration (500 mg/dL) in vitro increased ET-1 production by normal glomeruli but not diabetic glomeruli, and insulin partly suppressed ET- 1 production by diabetic glomeruli. The in vivo study demonstrated that when diabetic rats were injected daily with superoxide dismutase or catalase after diabetes was induced, the basal production of ET-1 was markedly attenuated after 1 week and 1 month, respectively. These results indicate that exogenously or endogenously derived ROS can enhance ET-1 production by diabetic rat glomeruli and that ROS scavengers suppress ET- 1 production both in vitro and in vivo. The effects of ROS on ET-1 production of diabetic glomeruli may be partly caused by the effect of hyperglycemia or insulin deficiency.
 ...
PMID:Reactive oxygen species enhances endothelin-1 production of diabetic rat glomeruli in vitro and in vivo. 1077 44

A high blood concentration of endothelin (ET)-1 may participate in the onset and progress of diabetic microangiopathy, resulting in neuropathy. We examined the therapeutic effects of prostaglandin E1 (PGE1), which possesses both a peripheral vasodilating action and inhibition of platelet aggregation, on diabetic microangiopathy. Increases in both skin temperature and peripheral never conduction velocity in diabetic patients were recorded four weeks after Lipo PGE1 administration. A quantitative decrease in urinary albumin concentration was also observed, suggesting its efficacy of action was on diabetic nephropathy. Lipo PGE1 administration reduced the elevated circulating plasma ET-1 levels in the diabetic patients. As an increase in ET-1 concentrations is thought to correlate with the onset and progress of diabetic microangiopathy, the reduction of plasma ET-1 concentration by Lipo PGE1 administration may be one reason for the improvement in diabetic neuropathy and nephropathy.
 ...
PMID:The therapeutic effect of lipo PGE1 on diabetic neuropathy-changes in endothelin and various angiopathic factors. 1157 85

Two endothelium-derived factors, endothelin (ET), a vasoconstrictor, and vascular endothelial growth factor (VEGF), an angiogenic factor are thought to be involved in the pathogenesis of diabetic vascular complications. The aim of this study was to determine the effects of an angiotensin II type I (AT-1) receptor antagonist and an ACE inhibitor on the pathogenesis of VEGF and ET-1-mediated kidney disease in STZ-induced diabetic rats. Two days after STZ administration, diabetic rats were treated for 8 weeks with enalapril maleate, an ACE inhibitor, candesartan cilexetil, an AT-1 receptor antagonist, or saline. Urinary albumin and N-acetyl beta-D glucosaminidase (NAG) excretion as well as the VEGF protein content in the kidney were all found to be elevated in diabetic rats. Administration of enalapril maleate or candesartan cilexetil decreased the level of microalbuminuria and NAG excretion in diabetic rats. Administration of enalapril maleate also suppressed the elevated renal VEGF protein content in these animals while candesartan cilexetil treatment had no effect. Serum ET-1 and VEGF levels were unchanged by these treatments. These data support a role for AT-1 receptor antagonists and ACE inhibitors in the prevention of diabetic nephropathy, and suggest that the former may work by reducing renal VEGF levels.
 ...
PMID:Possible role of VEGF in the progression of kidney disease in streptozotocin (STZ)-induced diabetic rats: effects of an ACE inhibitor and an angiotensin II receptor antagonist. 1530 28

The endothelin (ET) system has been implicated in the pathogenesis of diabetic nephropathy. The role of the ET-B receptor (ETBR) is still unclear. The effect of ETBR deficiency on the progression of diabetic nephropathy in a streptozotocin model was analyzed in four groups: (1) Homozygous ETBR-deficient (ETBRd) diabetic rats, (2) ETBRd rats, (3) diabetic controls, and (4) wild-type controls. BP and kidney function were measured for 10 wk, followed by biochemical and histologic analysis of the kidneys. The study demonstrates that ETBRd diabetic rats on a normal-sodium diet develop severe hypertension, albuminuria, and a mild reduction of creatinine clearance. The strong BP rise seems not to be caused by activation of the renin-angiotensin-aldosterone system or by suppression of the nitric oxide system. Elevated plasma ET-1, possibly reflecting a reduced ETBR-dependent clearance, seems to cause the severe hypertension via the ETA receptor. The results do not support the hypothesis that a reduction of ETBR activity inhibits the progression of diabetic nephropathy. The study demonstrates for the first time that the combination of diabetes and ETBR deficiency causes severe low-renin hypertension with progressive renal failure.
 ...
PMID:Diabetic endothelin B receptor-deficient rats develop severe hypertension and progressive renal failure. 1649 78

We aimed to investigate the effects of Liuwei Dihuang decoction (LW) on the endothelin-1-reactive oxidative species (ET-ROS) system and matrix metalloproteinases (MMPs) in the early diabetic nephropathy induced by streptozotocin (STZ) in rats. Rats were divided into six groups as follows: the control group, the untreated model group, the treated groups with the LW (5, 10 and 15 g kg(-1), p.o.) and the aminoguanidine-treated group (100 mg kg(-1), orally). The treatment was performed for 4 weeks, beginning on the fifth week after one intraperitoneal injection of STZ (65 mg kg(-1)). In the untreated model group, increased blood glucose, decreased plasma insulin level and an impaired renal function were observed. There was an altered redox system shown by an increased malondialdehyde and decreased activity of glutathione peroxidase and superoxide dismutase in the renal cortex. An enhanced inducible nitric oxide synthetase, total nitric oxide synthase and constitutive nitric oxide synthase and a declined nitric oxide were found. An increased extracellular matrix was indicated by an abnormality of MMP-2 and MMP-9 activities and an increase in hydroxyproline. An up-regulated ET-1 level and increased mRNA expression of endothelin-converting enzyme, preproET-1 and ET( A) receptor were presented in the affected renal cortex, but no change in ET(B) receptor mRNA. The LW was most effective in reversing these changes in diabetic rats and was as effective as aminoguanidine. The benefits of the extracts in relieving the abnormalities in early diabetic nephropathy are likely to be mediated by suppression of the renal ET-ROS system and escalating the activity of MMPs.
 ...
PMID:Protective effect of Liuwei Dihuang decoction on early diabetic nephropathy induced by streptozotocin via modulating ET-ROS axis and matrix metalloproteinase activity in rats. 1940 9


1 2 3 Next >>