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)

Besides diabetic patients are controlled with glycosylated hemoglobins not exceeding 7% and the normalization of blood pressure with some hypotensive drugs, it has been noted the important role of protein restriction in diet in order to retard nephropathy progression. For some years, various aldose reductase inhibitors (ARIs) have been used, which avoid the accumulation of sorbitol in tissues as well as complications. Platelet antiaggregants are also used for the treatment of diabetic nephropathy, but at a lower level.
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PMID:[The treatment of incipient diabetic nephropathy (2nd of 2 parts)]. 876 75

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

By permitting the separation of increased aldose reductase activity from hyperglycaemia and insulin deficiency, galactose-fed rats have constituted a useful model for investigating diabetic complications. Such rats manifest an impaired afferent arteriolar responsiveness to pressure similar to that of rats 4 to 6 weeks after induction of diabetes with streptozotocin. In the present study, we investigated whether treatment of galactose-fed rats with the aldose reductase inhibitor tolrestat prevent this autoregulatory defect and whether the blunted afferent arteriolar responsiveness to pressure is associated with impaired responsiveness to angiotensin II. Pressure-induced vasoconstriction of afferent arterioles was assessed in kidneys made hydronephrotic to allow direct visualization of renal microvessels by computer-assisted image processing. Vessel diameters were quantitated following stepwise increments of renal perfusion pressure (RAP; from 80 to 180 mm Hg) in kidneys of control rats and rats fed a diet for 2 weeks with 50% galactose with or without tolrestat. Subsequent to the pressure studies, angiotensin II (0.3 nmol/l) was added to the perfusate, and vessel diameters were reassessed. Control rats exhibited progressive afferent arteriolar vasoconstriction when RAP was increased from 80 to 180 mm Hg (-17.2 +/- 1.0%; p < 0.001). In contrast, myogenic responses to increases in pressure were absent in the arterioles of the galactose-fed rats (-4.1 +/- 1.9%; N.S.). Treatment with tolrestat completely prevented this impairment in afferent arteriolar responsiveness (-16.5 +/- 1.8%; p < 0.001). The angiotensin II-induced vasoconstriction did not differ between control rats and galactose-fed rats. We conclude that increased aldose reductase activity contributes to impaired renal auto-regulation in galactose-fed rats, a model of diabetic nephropathy, but is not involved in the loss of afferent arteriolar responsiveness to angiotensin II.
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PMID:Impairment of afferent arteriolar myogenic responsiveness in the galactose-fed rat is prevented by tolrestat. 885 12

Hyperglycemia is of central importance in the pathogenesis of the complications of diabetes mellitus. Glucose activation of the polyol pathway may lead to renal arteriolar smooth muscle and glomerular mesangial cell hypocontractility. In the streptozotocin-induced diabetic rat, the effect of the aldose reductase inhibitor, tolrestat, in preventing glomerular hyperfiltration, renal hypertrophy, extracellular matrix accumulation, and mesangial cell hypocontractility was addressed. Streptozotocin-induced diabetic rats were followed for 12 weeks and half received tolrestat (25 mg/kg per day). Increased glomerular filtration rate was prevented by tolrestat (3.1 +/- 0.3 vs. 1.8 +/- 0.2 mL/min, diabetes vs. diabetes + tolrestat, p < 0.01), in part by reduction of the filtration fraction (0.39 +/- 0.03 vs. 0.29 +/- 0.01, diabetes vs. diabetes + tolrestat, p < 0.01). Tolrestat prevented the raised albumin excretion rates (3594 +/- 1154 vs. 713 +/- 161 mg/24 h, diabetes vs. diabetes + tolrestat, p < 0.01). Endothelin-1-induced contraction of isolated glomeruli was normal in tolrestat-treated diabetic animals compared with the hypocontractile diabetic glomeruli. Tolrestat prevented glomerular hypertrophy (1.86 +/- 0.10 vs. 1.49 +/- 0.03 microns 2 x 10(5), diabetes vs. diabetes + tolrestat, p < 0.001) and attenuated the accumulation of basement-membrane-like material (50.2 +/- 0.4% vs. 46.4 +/- 0.8%, diabetes vs. diabetes+tolrestat, p < 0.001). Fractional mesangial expansion was unchanged in tolrestat-treated diabetic rats compared with untreated animals. Tolrestat prevents the functional changes of glomerular hyperfiltration, mesangial cell hypocontractility, and increased glomerular permeability to albumin. Polyol accumulation may have differential effects on glomerular growth and extracellular matrix accumulation in early diabetic nephropathy.
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PMID:Prevention of early glomerulopathy with tolrestat in the streptozotocin-induced diabetic rat. 888 41

Recent studies suggest that the gene encoding aldose reductase (ALR2), the enzyme that converts glucose to sorbitol, may confer susceptibility to microvascular disease. DNA from 275 British Caucasian patients with type I diabetes and 102 normal healthy control patients were typed for a (CA)n dinucleotide repeat polymorphic marker in the 5'-region of the ALR2 gene using polymorase chain reaction (PCR). A highly significant decrease in the frequency of the Z+2 allele was found in patients with nephropathy (nephropathy group) compared with those with no complications after a 20-year duration of diabetes (uncomplicated group) (12.7 vs. 38.2%, respectively, chi2 = 18.6, P < 0.00001); this was accompanied by an increase in the Z-2 allele in the nephropathy group (32.0 vs. 12.7% in the uncomplicated group). The nephropathy group also had a significant decrease in the Z/Z+2 genotype compared with the uncomplicated patients (10.7 vs. 44.7%, chi2 = 16.0, P < 0.0001) and an increased frequency of the Z/Z-2 genotype. There was no significant association with diabetic retinopathy. These results demonstrate that the ALR2 gene may play a role in susceptibility to diabetic nephropathy; individuals with the Z+2 allele are more than seven times less likely to develop diabetic renal disease than those without this marker. This marker may prove valuable in screening for patients with diabetic nephropathy at diagnosis of diabetes.
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PMID:Polymorphism in the 5'-end of the aldose reductase gene is strongly associated with the development of diabetic nephropathy in type I diabetes. 900 Jul 6

Activation of the polyol pathway under hyperglycemic conditions is proposed to contribute to the development of diabetic nephropathy. The mechanisms by which this activation may lead to functional and structural changes within the kidney are yet to be definitively established. We have examined in vitro the steps linking increased polyol pathway activity resulting from hyperglycemia to prostaglandin production. Following the demonstration of increased prostaglandin E (PGE) levels in glomeruli from diabetic rats (14.9 +/- 2.5 v 59.1 +/- 19.4 ng PGE/mg protein), a specific inhibitor of aldose reductase, HOE-843, was used in vitro to analyze the response to hyperglycemia of the steps preceding prostaglandin production. In explants of glomeruli from control animals, increasing the glucose concentration in vitro from 5.6 mmol/L to 25 mmol/L resulted in a significant increase in the flux of glucose through the pentose phosphate pathway ([PPP] 1.29 +/- 0.08 v 2.00 +/- 0.11 nmol/h), de novo diacylglycerol synthesis (2.2 +/- 0.1 v 3.1 +/- 0.2 micromol/mg protein), membrane protein kinase C (PKC) activity (18.7 +/- 0.5 v 24.3 +/- 0.75 pmol/microg protein), and in vitro phospholipase A2 (PLA2) activity (2.18 +/- 0.46 v 3.83 +/- 1.07 nmol arachidonic acid hydrolyzed/min/mg cytosolic protein). For all parameters measured, the increase resulting from the increased glucose concentration could be prevented by in vitro addition of HOE-843 for 24 hours before measurement. These findings provide evidence to suggest a mechanism linking increased polyol pathway activity and an increase in PLA2 activity to increased prostaglandin production, which is observed in diabetes of recent onset and may ultimately lead to changes associated with the development of diabetic nephropathy.
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PMID:Effect of inhibition of aldose reductase on glucose flux, diacylglycerol formation, protein kinase C, and phospholipase A2 activation. 900 67

Diabetic nephropathy is the single most common cause of end-stage renal disease in the United States. Recently, several major therapeutic interventions have been developed and shown to slow or halt the progression of renal failure in patients with diabetes and diabetic kidney disease. Studies have shown that in patients with insulin-dependent diabetes and proteinuria, lowering systemic blood pressure slows the rate of decline in renal function and improves patients' survival. In the recently completed trial of angiotensin converting enzyme (ACE) inhibition in diabetic nephropathy, ACE inhibitors were specifically shown to decrease dramatically the risk of doubling of serum creatinine or reaching a combined outcome of end-stage renal disease or death independent of their effect on systemic blood pressure. In studies with small numbers of patients, dietary protein restriction has also been shown to slow the rate of decline of renal function. New potential interventions currently undergoing study include treatment with aldose reductase inhibitors, treatment with inhibitors of the formation of advanced glycosylation end-products, treatment of dyslipidemia, and a variety of other less well-studied interventions.
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PMID:Therapeutic interventions for nephropathy in type I diabetes mellitus. 914 77

Hypertension and diabetes mellitus are common chronic conditions which frequently coexist. Diabetic nephropathy is a major cause of elevated blood pressure in patients with insulin-dependent diabetes mellitus (IDDM). Diabetic nephropathy, arterial sclerosis, obesity and association of essential hypertension can be the causes of hypertension in patients with non-insulin-dependent diabetes mellitus (NIDDM). Ambulatory blood pressure monitoring has revealed that the nocturnal fall of blood pressure is blunted in patients with diabetic nephropathy. A blunted diurnal blood pressure variation is seen in microalbuminuric diabetic patients and even in some normoalbuminuric patients. Accumulating data suggest that normalisation of blood pressure in hypertensive IDDM patients is most important to minimise the loss of kidney function. Angiotensin converting enzyme (ACE) inhibitors have been reported to be effective in postponing the development of nephropathy and in slowing its progression. Whether only ACE inhibitors have such beneficial renal effects on diabetic nephropathy is under discussion. While many studies have suggested that insulin resistance and hyperinsulinaemia are related to an elevated blood pressure in hypertensive patients, there does not seem to be enough evidence to prove that insulin per se can raise blood pressure in humans. Neither an insulin infusion within a physiological range nor sustained hyperinsulinaemia and insulin resistance (e.g. patients with insulinoma, cystic ovary syndrome) have been associated with an elevated blood pressure. Insulin resistance in some hypertensive patients may be a consequence of a decreased blood flow due to an increased peripheral resistance. Preliminary evidence suggests that low birth weight or impaired fetal growth is related to hypertension and NIDDM. Familial clustering of diabetic nephropathy suggests the contribution of genetic susceptibility and/or environmental inheritance. The frequent association of nephropathy with hypertension has led to research on the genes related to hypertension (ACE, angiotensinogen). Nevertheless, to date no reliable and clinically useful genetic marker has been found. Attempts to correct the metabolic abnormalities derived from diabetes are a new topic in the treatment of diabetic nephropathy. The effects of HMG CoA reductase inhibitors (antihypercholesterolaemic drugs), aldose reductase inhibitors (inhibitors of the polyol pathway) and glycation inhibitors (inhibitors of formation of advanced glycosylation end-products) on diabetic nephropathy have been evaluated in animal studies and in some clinical trials. Thus far, results with HMG CoA reductase and aldose reductase inhibitors have been somewhat conflicting. The potential therapeutic role of glycation inhibition in the treatment of diabetes deserves further study.
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PMID:Diabetic nephropathy. Its relationship to hypertension and means of pharmacological intervention. 925 79

Several glucose transporters have recently been identified in glomeruli, and in cultured glomerular cells. These include the facilitative glucose transporter isoforms GLUTs 1, 3 and 4, and sodium-glucose cotransport activity with characteristics of SGLT1. GLUTs 1, 3 and 4 are all high affinity, low capacity, facilitative glucose transporters which typically would be saturated at or near physiologic glucose concentrations. The SGLT transporter of mesangial cells is also a high affinity transporter which similarly could be saturated under normal glucose conditions. This suggests that in order for mesangial cells to take up excessive quantities of glucose in diabetes, changes in glucose transporter expression, translocation or activity may be required. Accordingly, recent investigations discovered positive-feedback regulation of the mesangial cell GLUT1 transporter by glucose, and a regulatory role for GLUT1 in glucose metabolism and extracellular matrix synthesis. Future investigations of glucose transporters in the pathogenesis of diabetic renal disease will now likely proceed in multiple directions, including but not limited to: (1) examination of their regulation by growth factors implicated in diabetic nephropathy, and the resultant effects on ECM synthesis; (2) determination of the mechanisms by which GLUT1 regulates the expression of aldose reductase, PKC, GLUT1, and other genes in the mesangial cell; and (3) Suppression of glucose transporters in attempts to prevent high glucose-induced diabetic glomerulosclerosis.
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PMID:Glucose transporters of the glomerulus and the implications for diabetic nephropathy. 928 9

Thickening and reduplication of the tubular basement membrane has been reported as an early event in diabetic nephropathy. In the current study we examined the effects of elevated D-glucose concentrations on human proximal tubular (HPTC) type IV collagen and fibronectin turnover. Incubation of confluent growth arrested HPTC with 25 mM D-glucose led to accumulation of both type IV collagen and fibronectin. This effect was maximal at 48 hours and represented a sevenfold increase for fibronectin (N = 4, P = 0.04), and a threefold increase for type IV collagen (N = 3, P = 0.03) over cells exposed to 5 mM D-glucose controls. This increase was not dependent on new gene transcription for either protein. Tissue inhibitor of metalloproteinases (TIMP 1 + TIMP 2) were induced following addition of 25 mM D-glucose, but not when cells were exposed to 5 mM D-glucose. Twenty-four hours after the addition of 25 mM D-glucose there was an eightfold increase in TIMP 1 (P = 0.009, N = 4), and a tenfold increase in TIMP 2 levels (P = 0.003, N = 4), over the control values for both inhibitors. The increase in both TIMP 1 and TIMP 2 in response to 25 mM D-glucose was abrogated in a dose dependent manner by the aldose reductase inhibitor sorbinil. Gelatin-substrate gel zymography showed increased activity of gelatinase A, but not of gelatinase B in response to the addition of 25 mM D-glucose to HPTC. The induction of gelatinase A was accompanied by increased gelatinase A mRNA expression, which was inhibited both by protein kinase C (PKC) depletion using PMA pre-treatment, and by the addition of a PKC inhibitor. These data demonstrate that the glucose-induced accumulation of type IV collagen and fibronectin is unrelated to increased gene transcription, but may involve alterations in the degradative pathway of these basement membrane constituents. Furthermore, the data demonstrate that glucose may simultaneously activate two intracellular pathways (the polyol pathway and a PKC dependent activation pathway), which are involved in mediating separate, complementary effects on cell function.
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PMID:Exposure of human renal proximal tubular cells to glucose leads to accumulation of type IV collagen and fibronectin by decreased degradation. 932 36


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