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)

Evaluations of glomerular mRNA levels encoding for PCNA, TNF-alpha, PDGF-A and -B chains, TGF-beta, IGF-I, bFGF, and EGF were made at 4, 12, and 24 wk after injection of STZ in Sprague-Dawley rats. The mRNA levels for PCNA, TNF-alpha, PDGF-B chain, TGF-beta, and bFGF increased with age in STZ-induced diabetic rats. At 24 wk after STZ injection, mRNA levels for PCNA, TNF-alpha, PDGF-B chain, TGF-beta, and bFGF were increased 3.8-fold, (P < 0.01), 4.2-fold (P < 0.01), 4.0-fold (P < 0.01), 5.2-fold (P < 0.001), and 3.6-fold (P < 0.01), respectively, in the glomeruli of diabetic rats when compared with control rats. In contrast, mRNA levels for IGF-I, PDGF-A chain, and EGF were not altered in glomeruli from diabetic and control rats throughout the experimental period. Insulin treatment partially ameliorated the increase in mRNA levels for PCNA, TNF-alpha, PDGF-B chain, TGF-beta, and bFGF in the glomeruli of diabetic rats. These data indicate that alterations in growth factor mRNA levels in glomeruli may be a manifestation of diabetic nephropathy, and that hyperglycemia or insulin deficiency may play a role in abnormal growth factor gene regulation.
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PMID:mRNA expression of growth factors in glomeruli from diabetic rats. 809 59

The effect of the angiotensin-converting enzyme inhibitor, perindopril, on functional and structural parameters of diabetic nephropathy has been compared with triple therapy (hydralazine, reserpine, and hydrochlorothiazide) in normotensive, STZ-induced diabetic Sprague-Dawley rats. Animal groups included control rats, diabetic rats treated with perindopril, diabetic rats receiving triple therapy, and untreated diabetic rats. Treatment was continued for 32 wk. Blood pressure reduction and severity of diabetes, as assessed by body weight and glycemic control were similar with both drug regimens. A similar rise in plasma renin activity occurred in the two groups receiving antihypertensive drugs, whereas the perindopril but not the triple therapy group had suppressed plasma angiotensin-converting enzyme activity. No significant difference was observed in renal function among the four groups. Diabetes was associated with a progressive increase in albuminuria, but this rise was ameliorated by both perindopril and triple therapy. No significant difference was noted in albuminuria between triple therapy and perindopril-treated diabetic rats. Diabetes was associated with glomerular basement membrane thickening, mesangial expansion, and glomerular volume. No glomerular ultrastructural parameter was affected by antihypertensive drugs. No specific benefit of angiotensin-converting enzyme inhibition over triple therapy could be detected in this normotensive model of diabetic nephropathy.
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PMID:The effects of perindopril and triple therapy in a normotensive model of diabetic nephropathy. 845 12

The changes of width and anionic sites of glomerular basement membrane (GBM) are considered early changes of diabetic nephropathy. Recent work suggests that the normal barrier to the penetration of renal glomerular basement membrane by anionic plasma proteins may depend in part on the existence of negatively charged sites within the membrane. We evaluated the relationship between the change of width, anionic sites of GBM and transferrinuria in diabetic rats and normal controls in 1, 3, 6 months after administration by STZ. Diabetic rats revealed a thicken GBM (0.40-0.44microns) and reduced anionic sites (16-12/1000nm GBM length) compared with control rats (0.22 microns, 20-22/1000 nm GBM lenth). Transferrinuria was also significantly greater in diabetic rats than normals (P < 0.01). The changes in anionic sites and transferrinuria represented defect of GBM charge barrier in early phase of diabetic nephropathy. Aminoguanidine attenuated the rise in transferrinuria and prevented GBM thickness and loss of anionie sites.
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PMID:[The relation between the changes of width and anionic sites of glomerular basement membrane and transferrinuria in rats]. 855 44

The present study was conducted in order to determine whether an aldose reductase inhibitor (ARI), epalrestat, prevents the progression of diabetic nephropathy in rats. Rats were made diabetic by intravenous injection of streptozotocin (STZ 50 mg/kg) and epalrestat (100 mg/kg) was administered orally through a gastric tube once daily for 4 weeks. Examination by electron microscope revealed that the number of anionic sites (AS) in the lamina rara externa per 1000 nm of glomerular basement membrane (GBM) was significantly decreased in diabetic rats compared to control values (17.6 + or - 0.4 vs. 21.9 + or -0.4, P < 0.01), whereas, significant recovery (20.3 + or - 0.7, P < 0.05) was observed after 4 weeks of epalrestat treatment. Urinary albumin excretion (UAE) rate was markedly increased in diabetic rats and the treatment resulted in its significant suppression from diabetic rats. In conclusion, administration of epalrestat to diabetic rats is capable of preventing a reduction in the number of AS in GBM which would ameliorate an increased permeability of the basement membrane leading to albuminuria.
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PMID:Effect of an aldose reductase inhibitor on glomerular basement membrane anionic sites in streptozotocin-induced diabetic rats. 883 31

We investigated the effects of a 3-week treatment with various combinations of angiotensin-converting enzyme inhibitor (ACEI) and B1 and B2 bradykinin receptor (B1R and B2R) antagonists (B1A and B2A) and AT1 receptor antagonist on ERK 1 and 2 phosphorylation in isolated glomeruli from streptozotocin-treated diabetic rats (STZ rats). Body weight, glycemia, and blood pressure were monitored. The rats were divided into nine groups: (1) control; and groups 2-9 were STZ treated with (3) insulin, (4) ACEI, (5) ACEI + B1A, (6) ACEI + B2A, (7) B2A, (8) B1A, (9) AT1 antagonist. ERK 1 and 2 phosphorylation and expression of B1R and B2R were assessed by Western blot analysis. ERK 1 and 2 phosphorylation was higher in STZ rats; this activation was normalized by insulin and reduced by ACEI but not by AT1 antagonist. The reduction of ERK 1 and 2 phosphorylation by the ACEI was reversed by B1A and B2A. The induction of B1R was confirmed by increased expression of mRNA and B1 receptor protein. Since ERK 1 and 2 phosphorylation is an early event in the induction of matrix secretion and hyperproliferation associated with diabetic nephropathy, activation of B1R and B2R appears to be a useful pharmacological target in the management of this pathology.
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PMID:Induction of B1 receptors in streptozotocin diabetic rats: possible involvement in the control of hyperglycemia-induced glomerular Erk 1 and 2 phosphorylation. 1202 68

The present study was designed to examine the development of hypertension in diabetic rats treated with streptozotocin (STZ, 1 mg/g bw). The rats were studied at 3, 6, 9, 12 and 15 weeks. From the third week the rats were divided in diabetic rats according their glycemias and controls, along 15 weeks. After the third week a group of rats showed increased urinary protein excretion (93, 134, 155 and 191%) compared to controls. In this group of rats the urinary kallikrein excretion was lower than control and the systolic blood pressure became significantly elevated between 3 and 6 weeks and persisted up to 15 weeks. On the other hand a group of diabetic rats were normotensive with urinary protein excretion similar to controls and urinary kallikrein lower compared to control but significantly higher compared diabetic hypertensive rats. These data suggest that the association of progressive diabetic nephropathy with abnormal endothelium-dependent vasodilation may produce a high prevalence of hypertensive diabetes.
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PMID:The diabetic nephropathy and the development of hypertension in rats. 1236 7

Data derived from animals and humans suggest that the onset of diabetes is associated with hemodynamic changes in the renal circulation leading to increased renal plasma flow (RPF), glomerular capillary hyperfusion, and an increased glomerular transcapillary hydraulic pressure gradient. The duration of diabetes is one of the most important factors in predicting the development of diabetic nephropathy. On the other hand, diabetic nephropathy has been associated with the degree of hyperglycemia; thus, hyperglycemia may therefore contribute to alterations in structure and function of the kidney. In the present paper, we investigated early alterations of renal function in C57BL/KSJ mdb male mice that were injected with sub-diabetogenic doses of STZ. Urinary protein excretion (UPE) increased significantly at 12 and 18-20 days after STZ with a glucose level of 4-6 mm/l; the progressive increase of glycemia was followed by a progressive increase of UPE. In a similar way, urinary nitrite (NO2-) was also significantly increased. Urinary kallikrein excretion started to increase at a level of 4-6 mmol/l blood glucose concentration (BGC) 8 days after administration of STZ, and kidney vascular permeability also increased following the increment of BGC. These results confirm the presence of early modifications of renal function prior to the clinical detection of diabetic hyperglycemia.
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PMID:The development of insulitis and the kallikrein-kinin system. 1248 7

Renal accumulation of advanced glycation end products (AGEs) has been linked to the progression of diabetic nephropathy. Cleavage of pre-formed AGEs within the kidney by a cross-link breaker, such as ALT-711, may confer renoprotection in diabetes. STZ diabetic rats were randomized into a) no treatment (D); b) treatment with the AGE cross-link breaker, ALT-711, weeks 16-32 (DALT early); and c) ALT-711, weeks 24-32 (DALT late). Treatment with ALT-711 resulted in a significant reduction in diabetes-induced serum and renal AGE peptide fluorescence, associated with decreases in renal carboxymethyllysine and RAGE immunostaining. Cross-linking of tail tendon collagen seen in diabetic groups was attenuated only by 16 weeks of ALT-711 treatment. ALT-711, independent of treatment duration, retarded albumin excretion rate (AER), reduced blood pressure, and renal hypertrophy. It also reduced diabetes-induced increases in gene expression of transforming growth factor beta1 (TGF-beta1), connective tissue growth factor (CTGF), and collagen IV. However, glomerulosclerotic index, tubulointerstitial area, total renal collagen, nitrotyrosine, protein expression of collagen IV, and TGF-beta1 only showed improvement with early ALT treatment alone. This study demonstrates the utility of a cross-link breaker as a treatment for diabetic nephropathy and describes effects not only on renal AGEs but on putative mediators of renal injury, such as prosclerotic cytokines and oxidative stress.
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PMID:The breakdown of preexisting advanced glycation end products is associated with reduced renal fibrosis in experimental diabetes. 1295 2

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.
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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

Diabetes mellitus is associated with altered iron homeostasis in both human and animal diabetic models. Iron is a metal oxidant capable of generating reactive oxygen species (ROS) and has been postulated to contribute to diabetic nephropathy. Two proteins involved in iron metabolism that are expressed in the kidney are the divalent metal transporter, DMT1 (Slc11a2), and the Transferrin Receptor (TfR). Thus, we investigated whether renal DMT1 or TfR expression is altered in diabetes, as this could potentially affect ROS generation and contribute to diabetic nephropathy. Rats were rendered diabetic with streptozotocin (STZ-diabetes) and renal DMT1 and TfR expression studied using semi-quantitative immunoblotting and immunofluorescence. In STZ-diabetic Sprague-Dawley rats, renal DMT1 expression was significantly reduced and TfR expression increased after 2 weeks. DMT1 downregulation was observed in both proximal tubules and collecting ducts. Renal DMT1 expression was also decreased in Wistar rats following 12 weeks of STZ-diabetes, an effect that was fully corrected by insulin-replacement but not by cotreatment with the aldose reductase inhibitor, sorbinil. Increased renal TfR expression was also observed in STZ-diabetic Wistar rats together with elevated cellular iron accumulation. Together these data demonstrate renal DMT1 downregulation and TfR upregulation in STZ-diabetes. Whilst the consequence of altered DMT1 expression on renal iron handling and oxidant damage remains to be determined, the attenuation of the putative lysosomal iron exit pathway in proximal tubules could potentially explain lysosomal iron accumulation reported in human diabetes and STZ-diabetic animals.
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PMID:Altered expression of iron transport proteins in streptozotocin-induced diabetic rat kidney. 1587 45


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