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)

Endothelial dysfunction is a prevalent phenomenon in non-insulin dependent diabetic (NIDDM) patients with hypertension and albuminuria, and may contribute to the development and progression of cardiovascular disease, which is the main cause of the high morbidity and mortality observed in these patients. Therefore the aim of our study was to evaluate whether inhibition of angiotensin-converting enzyme (with lisinopril 10-20 mg day-1) could ameliorate endothelial dysfunction more than reducing blood pressure with conventional antihypertensive treatment (atenolol 50-100 mg day-1), usually in combination with a diuretic. We performed a 12-month prospective, randomized, double-blind, parallel study in 43 hypertensive NIDDM patients with diabetic nephropathy (21 treated with lisinopril and 22 with atenolol). The following variables were measured: 24-h ambulatory blood pressure (ABP); transcapillary escape rate of albumin (TERalb; i.e. initial disappearance of intravenously injected 125I-labelled human serum albumin); serum concentrations of von Willebrand factor (vWF), using ELISA, and urinary albumin excretion rate (UAE). Data are presented for 32 patients (16 lisinopril and 16 atenolol; age 60 years, SD 8; 25 males) out of 35 who completed the study and had valid measurements of TERalb. At baseline the two groups were comparable; TERalb (8.5 (SEM 0.6) vs. 7.2 (0.4)%); vWF (2.09 (range 0.82-4.34) vs. 1.97 (0.95-3.86) IU ml-1; UAE 916 (x/divided by antilog SEM 1.3) vs. 1444 (1.2), and mean ABP 110 (SEM 3) vs. 113 (2) mmHg, in the lisinopril and atenolol group, respectively. During follow up, the mean ABP was equally reduced in the lisinopril and atenolol group, by 12 (SEM 2) vs. 10 (2) mmHg, respectively, TERalb decreased in the lisinopril group by 0.6 (SEM 0.7)%, whereas it increased in the atenolol group 1.5 (0.5)%; the mean difference was 2.2% (95% CI, 0.5 to 3.9; p = 0.015). UAE was reduced by 45% (95% CI, 25 to 60) in the lisinopril group vs. 10% (-15 to 30) in the atenolol group (p = 0.014). Serum vWF was not changed during follow up in either group. Our study suggests that lisinopril has both reno- and vasculoprotective properties in hypertensive NIDDM patients with diabetic nephropathy.
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PMID:Lisinopril improves endothelial dysfunction in hypertensive NIDDM subjects with diabetic nephropathy. 927 69

Albumin modified by Amadori glucose adducts, formed in increased amounts in diabetes, stimulates collagen IV production and gene expression in renal glomerular mesangial cells, and induces mesangial matrix accumulation accompanied by increased mRNA encoding alpha 1 (IV) collagen and fibronectin in diabetic animals. These effects contribute to the pathogenesis of diabetic nephropathy, and resemble biologic activities of the cytokine TGF-beta 1, which also has been causally implicated in diabetic renal disease. We postulated that Amadori-modified glycated albumin modulates TGF-beta 1 expression in mesangial cells, and that TGF-beta 1 participates in mediating the glycated albumin-induced increases in mesangial cell matrix production. To test this hypothesis, we measured mRNA encoding TGF-beta 1, the TGF-beta Type II receptor and fibronectin, a key matrix component of the TGF-beta 1 tissue response, after incubation of mesangial cells with glycated albumin. Steady state levels of the mRNAs encoding for these proteins were stimulated when mesangial cells were cultured in the presence of albumin containing Amadori glucose adducts compared with levels in cells cultured with the nonglycated, glucose-free counterpart. The glycated protein-induced changes in mRNA expression were observed with concentrations of glycated albumin encompassing those found in clinical specimens and in media containing physiologic (5.5 mM) glucose concentrations, indicating that they were due to the glucose-modified protein and not to a hyperglycemic milieu. Further, they were accompanied by increased translated fibronectin protein, which was prevented with TGF-beta neutralizing antibody, as was the glycated albumin-induced increase in fibronectin mRNA. The findings indicate that Amadori-modified glycated albumin stimulates mesangial cell TGF-beta 1 gene expression by mechanisms that are operative under normoglycemic conditions. These data provide the first link between elevated glycated serum albumin concentrations and increased TGF-beta 1 bioactivity in the pathogenesis of mesangial matrix accumulation in diabetes.
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PMID:Glycated albumin stimulates fibronectin gene expression in glomerular mesangial cells: involvement of the transforming growth factor-beta system. 950 8

Advanced glycation end-products (AGEs) are assumed to play a major role in the genesis of diabetic nephropathy and other diabetic complications. We studied the potential effect of AGEs on protein turnover and lysosomal proteinase activities in LLC-PK1 cells, a pig kidney proximal tubules cell line. Advanced glycated bovine serum albumin (AGE-BSA) was used as a model of AGEs and its action was compared to that of nonglycated BSA. AGE-BSA but not BSA (50 micromol/l) induced a significant increase in cell volume (BSA: 4870.6 +/- 74.8 fl, AGE-BSA: 5718.0 +/- 20.7 fl, p<0.01). Protein degradation rate was decreased by 13.8% after 48 hrs. incubation with AGE-BSA (p<0.01) while protein synthesis increased by 19,1%, (p<0.01). After incubation with AGE-BSA but not BSA activities of lysosomal cathepsins (B, L+B and H) decreased in a time- and dose-dependent fashion. This decline was neither caused by a shift in lysosomal pH outside the optimal range for cathepsins, nor by a direct inhibitory effect of AGEs modified proteins or peptides but most probably by inhibition of cathepsin B expression as measured by RT-PCR. It is supposed that impaired protease activities participated in decreased protein breakdown and cell enlargement. For the first time our data provide the evidence that AGEs induce hypertrophy of LLC-PK1 cells due to decreased protein breakdown resulting from reduced lysosomal proteinase activities with a concomitant stimulation of protein synthesis.
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PMID:Advanced glycated albumin impairs protein degradation in the kidney proximal tubules cell line LLC-PK1. 984 87

Prolonged incubation of proteins with reducing sugar produces advanced glycation end products (AGEs), which are implicated as factors for aging and diabetic complications. We previously demonstrated the presence of N(epsilon)-(carboxymethyl)lysine (CML), one of the main AGE structures, in human and animal tissues using a monoclonal anti-CML antibody (6D12). These findings suggest that CML structures present in vivo could serve as immunogens to generate autoantibodies. This suggestion was tested in the present study. First, plasma samples from diabetic rats reacted positively with AGE bovine serum albumin (BSA). These reactivities increased with the duration of diabetic states and were inhibited specifically by CML-BSA. Second, a fraction purified from plasma of diabetic patients, which bound to AGE-BSA, showed a positive reaction to CML-BSA and furthermore also to human lens proteins, which are known to undergo CML modification in vivo. Finally, patients with renal failure caused by diabetes or nondiabetic pathologies had a higher autoantibody activity against CML structure than that in normal subjects or diabetic patients without renal failure. These results indicate that CML accumulated in vivo serves as an immunological epitope to generate an autoantibody specific for CML that might be used as a potential marker for diabetic nephropathy or chronic renal failure.
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PMID:Autoantibody against N(epsilon)-(carboxymethyl)lysine: an advanced glycation end product of the Maillard reaction. 1048 Jun 17

Nonenzymatic glycation is increased in diabetes. Most studies so far have focused on the role of advanced glycation end products (AGEs) in vascular complications, whereas the role of early glycation Amadori-modified proteins, which is the predominant form of glycated proteins, has not been systemically investigated in humans. We developed an antiserum against glycated human serum albumin (HSA) and used this to study the role of early glycation products in vascular complications in type 1 diabetic patients. Amadori albumin was determined to be the recognition epitope of the antiserum. The antibody recognized a specific glucose adduct and a conformational component specific for human albumin in Amadori albumin, with no recognition of AGEs. Plasma Amadori albumin levels were significantly higher in type 1 diabetic patients (n = 55) than in healthy control subjects (n = 60) (39.2+/-9.9 vs. 20.9+/-4.0 U/ml, P < 0.0005). Amadori albumin correlated with levels of plasma markers of endothelial function von Willebrand factor (r = 0.29, P < 0.05) and vascular cell adhesion molecule-1 (r = 0.41, P < 0.005), but not soluble E-selectin. In addition, Amadori albumin immunoreactivity was detected in the capillaries of retinas of diabetic patients. Plasma levels of Amadori albumin were determined in a second group of type 1 diabetic patients with long-standing diabetes with (n = 199) or without (n = 192) diabetic nephropathy. Patients with nephropathy had higher Amadori albumin levels than did those without it (50.9+/-9.5 vs. 45.1+/-6.3 U/ml, P < 0.0005). Age-, sex-, and diabetes duration-adjusted analyses showed that nephropathy was significantly associated with Amadori albumin with an odds ratio (OR [95% CI]) of 1.11 [1.08-1.15] per U/ml increase. After additional adjustment for levels of creatinine, glycated hemoglobin, cholesterol, triglycerides, blood pressure, preexistent retinopathy, and cardiovascular disease, Amadori albumin continued to be significantly associated with nephropathy (OR 1.06 [1.01-1.11]) per U/ml increase. Our results are consistent with a proposed pathophysiological role of Amadori albumin in microvascular complications of type 1 diabetic patients.
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PMID:Amadori albumin in type 1 diabetic patients: correlation with markers of endothelial function, association with diabetic nephropathy, and localization in retinal capillaries. 1058 Apr 35

This study examined whether the prevention of diabetes-related albuminuria by aminoguanidine (AG) or ramipril (RAM) may be mediated by a common post-glomerular basement membrane renal intracellular mechanism involving protein kinase C (PKC). The renal handling of albumin was examined over 24 weeks in control and streptozotocin (STZ)-induced diabetic rats. A radioimmunoassay (RIA) that measures intact albumin, and intravenously injected tritium-labeled rat serum albumin, was used to assess the proportion of intact albumin and albumin fragments in urine. Diabetes was induced in male Sprague-Dawley rats by the intravenous administration of STZ at a dose of 50 mg/kg. Age-matched control rats received buffer alone. Diabetes was characterized by an increase in blood glucose (>15 mmol/l), an increase in GHb (means at 24 weeks 29.3+/-1.1%; control 6.1+/-0.1%, P<0.005), an increase in glomerular filtration rate (GFR) (4.13+/-0.15 ml/min; control 3.54+/-0.19 ml/min, P<0.005), an increase in intact albumin excretion rate (expressed as geometric mean 11.64 times/divided by 2.11 mg/24 h; control 0.74 times/divided by 1.57 mg/24 h, P<0.005) as measured by RIA, and an increase in glomerular PKC activity (26.83+/-2.38 pmol x mg(-1) x min(-1); control 14.6+/-2.99 pmol x mg(-1) x min(-1), P<0.005). Treatment of diabetic rats with either AG or RAM prevented the rise in intact albuminuria and glomerular PKC activity. Renal lysosomal cathepsin activity decreased in diabetic rats and this was not prevented by AG or RAM. Neither drug affected glycemic control or GFR, but RAM reduced systolic blood pressure (BP), whereas AG did not. These data indicate that urinary excretion of intact albumin and albumin-derived fragments in diabetes may be modulated independently of glycemic control (AG and RAM) and systolic BP (RAM). While both drugs are known for their different mechanisms of action, the fact that both prevent diabetes-related increases in glomerular PKC activity and albuminuria supports the hypothesis that PKC plays a central role in the development of diabetic nephropathy.
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PMID:Prevention of albuminuria by aminoguanidine or ramipril in streptozotocin-induced diabetic rats is associated with the normalization of glomerular protein kinase C. 1061 54

A 72-year-old woman with diabetic nephropathy was hospitalized with peripheral edema in the extremities and weight increase. After diuretics and human serum albumin administration, her condition improved. From the 15th day she had run a subfever and her breathing was diminished in the left lower lung field. A plain chest X-ray film showed pleural effusion over the left lung field. The fluid was exudative. Fluid cultures were negative. A tuberculin reaction was negative. Polymerase chain reaction method disclosed mycobacterium avium complex, indicating rare pleuritis due to mycobacterium avium complex. Eighteen days after chemotherapy, pleural effusion disappeared. Although her hemoglobin A1c (HbA1c) levels were maintained from 6.0 to 6.5% over 4 years, urinary albumin excretion levels and serum creatinine levels increased, indicating deteriorating diabetic nephropathy. Serum albumin levels remained low (3.3-3.6 g/dl). Malnutrition, impaired cellular immunity and apparently abnormal microvascular circulation due to diabetes mellitus may consequently have induced pleuritis due to mycobacterium avium complex.
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PMID:Mycobacterium avium complex pleuritis accompanied by diabetes mellitus. 1080 46

Advanced glycosylation end products (AGE) seem to be implicated in the pathogenesis of diabetic nephropathy. The present study has examined the effects of AGE on protein kinase C (PKC) activity and transforming growth factor-beta1 (TGF-beta1) in relation to collagen gene regulation in cultured human mesangial cells (HMCs). Quiescent HMCs were exposed to serum-free media containing bovine serum albumin (BSA), AGE-modified BSA (AGE-BSA), or glycated BSA in which AGE formation was prevented by the use of aminoguanidine (BSA-AM). AGE-BSA (200 microg/mL) induced a peak membrane-associated PKC activity, particularly PKC-a, at 4 hours. AGE-BSA stimulated alpha1(I) and alpha1(IV) collagen mRNA expression after 24-hour incubation with HMCs, which remained elevated until hour 60. HMCs incubated with AGE-BSA induced a significant inhibition of cell proliferation compared with cells incubated with BSA. AGE-BSA stimulated TGF-beta mRNA and protein expression in HMCs. The TGF-beta secreted by HMCs was shown by CCL-64 mink lung cell assay to be bioactive. In contrast, BSA-AM did not affect either collagen or TGF-beta mRNA or protein expression in HMCs. The stimulatory effects of AGE-BSA on collagen gene regulation in HMCs could be negated by the pretreatment of HMCs with GF 109203X for 30 minutes or with phorbol myristate acetate for 24 hours before AGE-BSA administration. Neutralizing antibody to TGF-beta inhibited increased collagen mRNA expression by HMCs exposed to AGE-BSA. These results suggest that AGE-BSA stimulates collagen mRNA expression by activating PKC and the transcriptional upregulation of TGF-beta1 in HMCs. Thus, PKC and TGF-beta may function as key signaling intermediaries in the AGE-up-regulated collagen gene expression pathway in HMCs.
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PMID:Advanced glycosylation end products stimulate collagen mRNA synthesis in mesangial cells mediated by protein kinase C and transforming growth factor-beta. 1143 29

The mortality among end-stage renal failure (ESRF) patients undergoing renal replacement therapy (RRT) remains high. An important proportion of these patients die shortly after the initiation of RRT. The present study aims to determine the best predictors for the early mortality in a group of 140 ESRF patients who initiated RRT between october 96 and december 99. The mean age of the study group was 61 +/- 13 years, and the mean follow-up time was 20 +/- 12 months. Diabetic nephropathy was the most prevalent etiology of renal failure (30%). The following data, collected immediately before the initiation of RRT, were included as independent variables: demographic and clinical characteristics, including the nutritional status established by the Subjective Global Assessment (SGA), follow-up time in the predialysis clinic (less or longer than 3 months), EPO therapy, vascular access, renal function (creatinine and urea clearances, and Kt/V urea), hematological and biochemical data including serum albumin, bicarbonate, transferrin, PTH and C-Reactive protein, as well as the protein catabolic rate and the percent of lean body mass normalized for ideal body weight, calculated from the 24 h total urine excretion of nitrogen and creatinine. The Cox proportional hazard regression model, stratified for an age over or less than 65 year, was utilized to determine the best predictors for the mortality during the study period. Sixty percent of patients had at least one comorbid condition, and 35% had cardiovascular diseases. Mild-moderate or severe malnutrition was observed in 48% of patients. The creatinine clearance and Kt/V urea before the initiation of RRT were: 9.50 +/- 2.64 ml/min/1.73 m2 and 1.47 +/- 0.44, respectively. Forty-one patients died during the study period (annual death rate: 17%). The best predictor of mortality was the nutritional status assessed by the SGA (OR: 2.32, IC 95% 1.54-3.48, p < 0.0001). In a second analysis in which the SGA was removed from the model, the previous history of cardiovascular diseases (OR: 2.07, CI 95%: 1.06-4.06, p = 0.032), and the percent of lean body mass/ideal weight (OR: 0.96; IC 95%: 0.93-0.99; p = 0.042), proved to be the best predictor of mortality. In conclusion, nutritional indices prior to the initiation of RRT, and the previous history of cardiovascular diseases were the best predictors of the early mortality in this unselected population on dialysis. Because nutritional status appeared to be a marker of the severity of the comorbid conditions, a better control of the number and severity of these comorbid conditions may be the best way for reducing the mortality in patients on RRT.
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PMID:[Predictors of early death during dialysis]. 1147 8

Familial aggregation of end-stage renal disease (ESRD) is frequently observed in the common causes of kidney failure. It is unknown whether the clinical course of nephropathy differs based on an individual's family history of ESRD. The ESRD Network 6 Family History of ESRD database was analyzed to compare dialytic survival among patients with first- or second-degree relatives on dialysis therapy (positive family history) with those lacking relatives with ESRD (negative family history). Study participants included 3,442 adult, black or white, incident patients with ESRD who initiated dialysis therapy in ESRD Network 6 facilities in 1995 and participated in the Network-sponsored Family History of ESRD study. All deaths were reported to the Network and used to calculate mortality rates. The relative risk for death was used to compare rates between levels of patient characteristics. Multivariate analyses used proportional hazards regression. Overall, 730 patients (21.2%) had a positive family history of ESRD. Black patients, those who were younger at the onset of ESRD, patients with greater degrees of functional status, and women were more likely to have a positive family history. During 9,000 patient-years of follow-up, 1,599 patients died (17.8 deaths/100 dialysis-years). Univariate analyses showed that patients with a positive family history of ESRD had 20% lower mortality than those with a negative family history of ESRD (relative risk, 0.80; 95% confidence interval, 0.7 to 0.9; P = 0.001). Older age, white race, diabetic nephropathy, lower functional status, lower serum albumin level, congestive heart failure, and ischemic heart disease also were associated with greater mortality rates. Multivariate analyses showed that only older age at onset of ESRD, white race, low functional status, ESRD caused by diabetes, and congestive heart failure were associated with increased mortality. A family history of ESRD in either first- or second-degree relatives was no longer a significant determinant of survival. We conclude that familial clustering of ESRD does not significantly impact on dialytic survival after controlling for the competing effects of patient race, age of ESRD onset, and the presence of diabetes mellitus.
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PMID:Family history of end-stage renal disease does not predict dialytic survival. 1153 87


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