UMLS:C0033687 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rosiglitazone (BRL 49653), a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist and potent insulin action-enhancing agent, was given in the diet (50 micromol/kg of diet) to male Zucker rats ages 6-7 weeks for 9 months (prevention group). In this treatment mode, rosiglitazone prolonged the time to onset of proteinuria from 3 to 6 months and markedly reduced the rate of its subsequent progression. Progression was also retarded when treatment was commenced (intervention group) after proteinuria had become established (4 months; ages 24-25 weeks). In either treatment mode, rosiglitazone normalized urinary N-acetyl-beta-D-glucosaminidase activity, a marker for renal proximal tubular damage, and ameliorated the rise in systolic blood pressure that occurred coincidentally with the development of proteinuria in Zucker fatty control rats. The renal protective action of rosiglitazone was verified morphologically. Thus in the prevention group there was an absence of the various indexes of chronic nephropathy that were prominent in the Zucker fatty control group, namely, glomerulosclerosis, dilated tubules containing proteinaceous casts, a loss of functional microvilli on the tubular epithelium, and varying degrees of chronic interstitial nephritis. An intermediate pathology was observed in the intervention group. Also, pancreatic islet hyperplasia, ultrastructural evidence of beta-cell work hypertrophy, and derangement of alpha-cell distribution within the islet were prominent features of Zucker fatty control rats, but these adaptive changes were ameliorated (intervention group) or prevented (prevention group) by rosiglitazone treatment. These data demonstrate that treatment of Zucker fatty rats with rosiglitazone produced substantial protection over a prolonged period against the development and progression of renal injury and the adaptive changes to pancreatic islet morphology caused by sustained hyperinsulinemia.
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PMID:Peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone, protects against nephropathy and pancreatic islet abnormalities in Zucker fatty rats. 970 35

The Pro12Ala polymorphism of the gene encoding the peroxisome proliferator-activated receptor (PPAR)-gamma2 has recently been shown to be associated with type 2 diabetes. In the present analysis, we investigated whether PPAR-gamma2 Pro12Ala was associated with microvascular complications of type 2 diabetes, such as albuminuria, end-stage renal failure (ESRF), or retinopathy. A total of 445 patients with type 2 diabetes who were enrolled in the Berlin Diabetes Mellitus Study and in whom we determined albuminuria and the presence of ESRF and retinopathy were genotyped for the PPAR-gamma2 Pro12Ala polymorphism. We also measured potentially important covariables, such as blood pressure, BMI, duration of diabetes, glycosylated hemoglobin, serum creatinine, and serum lipids. Among 445 patients with type 2 diabetes (mean age 59.3 years), the Pro12Ala genotype distribution was in Hardy-Weinberg equilibrium (P = 0.42). The Ala12 allele frequency was 0.14. With adjustment for covariables, the 118 Ala12 allele carriers had significantly lower urinary albumin excretion (UAE) than the 327 noncarriers (17.1 vs. 25.8 mg/d; P = 0.01). The percentage decrease in UAE observed in PPAR-gamma Ala12 allele carriers relative to noncarriers (P = 0.003) rose from 0.2% (P = 0.99) to 54% (P = 0.008) and to 70% (P = 0.01) when the duration of diabetes increased from <10 years to 10-19 years and to >or=20 years, respectively. Similarly, the odds ratios of having albuminuria decreased from 1.22 (P = 0.54) to 0.61 (P = 0.23) and to 0.11 (P = 0.007), respectively. Among patients with type 2 diabetes, PPAR-gamma2 Ala12 allele carriers had significantly lower UAE and tended to develop overt proteinuria less frequently. These observations suggest a protective effect of the Ala12 allele in relation to diabetic nephropathy.
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PMID:Peroxisome proliferator-activated receptor-gamma2 polymorphism Pro12Ala is associated with nephropathy in type 2 diabetes: The Berlin Diabetes Mellitus (BeDiaM) Study. 1214 84

The peroxisome proliferator-activated receptor gamma2 (PPARgamma2) Pro12Ala polymorphism has been associated with a decreased risk of type 2 diabetes and a lower albumin excretion rate (AER) in patients with established diabetes. We performed a case-control study aiming to evaluate the association between the Pro12Ala polymorphism and diabetic nephropathy. Genomic DNA was obtained from 104 type 2 diabetic patients (case subjects) with chronic renal insufficiency (78 on dialysis and 26 with proteinuria [AER >or=200 microg/min] and serum creatinine >or=2.0 mg/dl) and 212 normoalbuminuric patients (AER <20 microg/min) with known diabetes duration >or=10 years (control subjects). The genotypic distribution of the PPARgamma2 Pro12Ala polymorphism in these diabetic patients was in Hardy-Weinberg equilibrium, and the Ala allele frequency was 9%. The frequency of Ala carriers (Ala/Ala or Ala/Pro) was 20.3% in control subjects and 10.6% in case subjects (P = 0.031). The odds ratio of having diabetic nephropathy for Ala carriers was 0.465 (95% CI 0.229-0.945; P = 0.034). Carriers of the Ala allele were not different from noncarriers (Pro/Pro) regarding sex (38.9 vs. 44.1% males) or ethnicity (77.4 vs. 71.7% white) distribution, age (61 +/- 10 vs. 61 +/- 10 years), known diabetes duration (17 +/- 7 vs. 16 +/- 7 years), BMI (27 +/- 4 vs. 28 +/- 5 kg/m(2)), fasting plasma glucose (184 +/- 81 vs. 176 +/- 72 mg/dl), HbA(1c) (6.7 +/- 2.3 vs. 6.9 +/- 2.4%; high-performance liquid chromatography reference range: 2.7-4.3%), and systolic (145 +/- 27 vs. 0.144 +/- 24 mmHg) or diastolic (87 +/- 14 vs. 85 +/- 14 mmHg) blood pressure, respectively. In conclusion, the presence of the Ala allele may confer protection from diabetic nephropathy in patients with type 2 diabetes.
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PMID:The human peroxisome proliferator-activated receptor gamma2 (PPARgamma2) Pro12Ala polymorphism is associated with decreased risk of diabetic nephropathy in patients with type 2 diabetes. 1463 65

Adiponectin appears to be an important modulator for metabolic and vascular diseases. A case-controlled study was designed to measure plasma adiponectin levels and investigate the effects of rosiglitazone on adiponectin levels in type 2 diabetic patients with proteinuria. Sixty-four patients (mean age, 46.1+/-4.6 yr; 30 male, 34 female) and 26 healthy volunteers (mean age, 45.3+/-4.8 yr; 14 male, 12 female) were included. Patients with proteinuria were treated with 4-mg/d rosiglitazone (n=21, 10 males, 11 females) for 4 wk. Adiponectin levels in patients were significantly lower than those of controls (p<0.001). There were significant negative correlations between adiponectin concentrations and insulin levels as well as homeostasis model assessment (HOMA) index in patient's group (r=-<FONT "Optima">0.538, p<0.001; r=-<FONT "Optima">0.393, p=0.001, respectively). There was also a significant negative correlation between plasma adiponectin concentrations and the degree of proteinuria (r=-<FONT "Optima">0.526, p=0.002). Plasma adiponectin levels in patients with proteinuria (n=31; 3.91+/-2.57 microg/mL) were significantly lower than those without proteinuria (n=33; 10.15+/-1.97 microg/mL) (p<0.001). After the treatment period, adiponectin levels significantly increased (p<0.001) and proteinuria, plasma insulin, and HOMA indexes significantly decreased in treatment group (p<0.001, p<0.001, p<0.001, respectively). The results suggest that adiponectin is inversely correlated with proteinuria and treatment with peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist rosiglitazone both corrects proteinuria and increases the low adiponectin levels in diabetic patients.
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PMID:Peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonist increases plasma adiponectin levels in type 2 diabetic patients with proteinuria. 1575 47

Obesity-related glomerulopathy (ORG) is an important complication of obesity. The pathophysiological mechanism of glomerular injury in ORG is incompletely understood. Gene expression profiles in the glomeruli obtained from renal biopsy samples of patients with ORG were investigated, using a microdissection technique combined with Affymetrix microarray analysis. Six patients presented with obesity, proteinuria, and biopsy-proven ORG were enrolled. Two sex- and age-matched donor kidneys were applied as the controls. Glomeruli were dissected out from renal biopsy samples under microscope, and total RNA was extracted using RNeasy Micro kit. After two rounds of T7 promoter-based RNA amplification, gene expression profiles of the glomeruli samples were detected using Affymetrix U133A gene chips. Bioinformatic tools were applied to analyze the microarray data. Results of candidate ORG-related genes were further confirmed by real-time quantitative PCR and immunohistochemistry staining using renal biopsy samples of a larger pool of 15 ORG patients. Genes related to lipid metabolism, inflammatory cytokines, and insulin resistance were the most highlighted subgroups that significantly changed in the glomerular gene expression profiles of the ORG patients, compared with the controls. The expression levels of several key genes in lipid metabolism were increased over 2-fold, including low-density lipoprotein receptor, fatty acid binding protein 3, and sterol regulatory element binding protein 1. Moreover, some inflammatory cytokines and their downstream molecules were increased as well, including TNF-alpha and its receptors, IL-6 signal transducer, and interferon-gamma. As the indicators of insulin resistance in the local glomerular cells, levels of glucose-transporter 1, leptin receptor, peroxisome proliferator-activated receptor-gamma, and vascular endothelial growth factor increased, too. In addition to lipid dysmetabolism and insulin resistance, the activation of an inflammatory process in the glomeruli might play a unique role in the development of obesity-related glomerulopathy. Our results expand the understanding of obesity-induced glomerular injuries and shed light on new approaches in the treatment of this disease.
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PMID:Obesity-related glomerulopathy: insights from gene expression profiles of the glomeruli derived from renal biopsy samples. 1621 Mar 74

The renoprotective potential of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist pioglitazone was explored in an immune model of progressive nephropathy, passive Heymann nephritis (PHN), compared with that of an angiotensin II receptor antagonist, taken as standard therapy for renoprotection. PHN rats received orally vehicle, pioglitazone (10 mg/kg twice daily), or candesartan (1 mg/kg twice daily) from months 2 to 8. Pioglitazone reduced proteinuria as effectively as candesartan and limited renal functional and structural changes. Kidneys from untreated PHN rats showed lower nephrin mRNA and protein than controls, both restored by pioglitazone. The effect was seen both early and late during the course of the disease. Whether the antiproteinuric effect of pioglitazone could be due to its effect on nephrin gene transcription also was investigated. HK-2 cells were transfected with plasmids that harbor the luciferase gene under portions (2-kb or 325-bp) of human nephrin gene promoter that contain putative peroxisome proliferator-responsive elements (PPRE) and incubated with pioglitazone (10 muM). Transcriptional activity of luciferase gene was highly increased by pioglitazone, with the strongest expression achieved with the 325-bp fragment. Increase in luciferase activity was prevented by bisphenol A diglycidyl ether, a PPAR-gamma synthetic antagonist. Electrophoretic mobility shift assay experiments showed a direct interaction of PPAR/retinoid X receptor heterodimers to PPRE present in the enhancer region of the nephrin promoter. In conclusion, pioglitazone exerts an antiproteinuric effect in immune-mediated glomerulonephritis as angiotensin II receptor antagonist does. Enhancement of nephrin gene transcription through specific PPRE in its promoter discloses a novel mechanism of renoprotection for PPAR-gamma agonists.
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PMID:Transcriptional regulation of nephrin gene by peroxisome proliferator-activated receptor-gamma agonist: molecular mechanism of the antiproteinuric effect of pioglitazone. 1668 28

In Akita and OVE26 mice, two genetic models of type 1 diabetes, diabetic nephropathy is characterized by mesangial expansion and loss of podocytes, resulting in glomerulosclerosis and proteinuria, and is associated with increased expression of profibrotic growth factors, proinflammatory cytokines, and increased oxidative stress. We have also found significant increases in renal triglyceride and cholesterol content. The increase in renal triglyceride content is associated with 1) increased expression of sterol regulatory element-binding protein (SREBP)-1c and carbohydrate response element-binding protein (ChREBP), which collectively results in increased fatty acid synthesis, 2) decreased expression of peroxisome proliferator-activated receptor (PPAR)-alpha and -delta, which results in decreased fatty acid oxidation, and 3) decreased expression of farnesoid X receptor (FXR) and small heterodimer partner (SHP). The increase in cholesterol content is associated with 1) increased expression of SREBP-2 and 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase, which results in increased cholesterol synthesis, and 2) decreased expression of liver X receptor (LXR)-alpha, LXR-beta, and ATP-binding cassette transporter-1, which results in decreased cholesterol efflux. Our results indicate that in type 1 diabetes, there is altered renal lipid metabolism favoring net accumulation of triglycerides and cholesterol, which are driven by increases in SREBP-1, ChREBP, and SREBP-2 and decreases in FXR, LXR-alpha, and LXR-beta, which may also play a role in the increased expression of profibrotic growth hormones, proinflammatory cytokines, and oxidative stress.
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PMID:Regulation of renal fatty acid and cholesterol metabolism, inflammation, and fibrosis in Akita and OVE26 mice with type 1 diabetes. 1693 98

The novel hypoglycemic agent, YM440 ((Z)-1,4-bis{4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl) methyl] phenoxy}but-2-ene) is a ligand of the peroxisome proliferator-activated receptor, (PPAR) gamma. YM440 has been shown to counteract insulin resistance in diabetic rodent models. However, it is not clear whether this compound has a significant effect on hyperlipidemia in vivo. Hyperlipidemia has been reported to be a risk factor for the early development of renal disease. The aim of this study is to examine the effects of chronic treatment with YM440 on hyperlipidemia and renal injury in obese Zucker fatty (ZF) rats. Treatment of 8-week-old ZF rats with YM440 (100 mg/kg/day) for 16 weeks decreased plasma triglyceride and cholesterol concentrations. YM440 markedly reduced the rate of progression of both albuminuria and proteinuria. YM440 normalized urinary N-acetyl-beta-D-glucosaminidase (NAG) activity, which is a marker for renal proximal tubular damage, and ameliorated the rise in systolic blood pressure compared to the vehicle control. YM440 also blocked the development of nephromegaly. Histological analyses revealed that both glomerular area expansion and tubular cast accumulation gradually lessened in YM440-treated ZF rats. Regression analyses between the plasma triglyceride levels and the renal parameters (urinary protein excretion and albumin excretion) indicated that the renal parameters correlated positively with the plasma triglyceride levels. In conclusion, the hypolipidemic effects of YM440 prevent renal injury in ZF rats. YM440 might be useful for preventing the early development of diabetic nephropathy in subjects with type 2 diabetes by ameliorating metabolic control problems.
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PMID:YM440, a novel hypoglycemic agent, protects against nephropathy in Zucker fatty rats via plasma triglyceride reduction. 1698 6

In the development of diabetic nephropathy, advanced glycation end products (AGEs) play a causative role via induction of extracellular matrix (ECM) accumulation. Plasminogen activator inhibitor-1 (PAI-1), as a major inhibitor of plasminogen activator that plays an important role in degrading ECM, was found to significantly increase in renal fibrotic diseases. Activation of peroxisome proliferator-activated receptor (PPAR)-gamma prevented diabetic nephropathy. The present study, therefore, was to define whether or not AGE-induced renal ECM accumulation and renal dysfunction are mediated by upregulation of PAI-1 expression and whether or not PPAR-gamma agonist can attenuate these AGE effects via suppressing PAI-1 expression. Rats were given AGEs alone by iv injection at 100 mg/kg daily with or without oral supplementation of PPAR-gamma agonist rosiglitazone (RGZ) at 2 mg/kg daily for 6 weeks. Results showed that AGEs induced a renal ECM accumulation, as shown by increases in periodic acid-Schiff-positive materials, fibronectin, and type IV collagen (Col IV) contents in glomeruli, and a mild renal dysfunction, as shown by an increase in urinary proteins. AGEs also caused an increase in PAI-1 expression and a decrease in plasminogen activator bioactivity in the kidney. Treatment with RGZ significantly ameliorated AGE-induced renal ECM accumulation, proteinuria, and PAI-1 upregulation. Direct exposure of rat mesangial cells to AGEs in vitro induced increases in fibronectin and Col IV syntheses along with an increase in PAI-1 expression, effects significantly attenuated by RGZ. Preincubation of PAI-1 antibody to AGE-treated mesangial cells completely prevented AGE-induced fibronectin and Col IV production. These results suggest that upregulation of PAI-1 expression plays a critical role in AGE-induced renal ECM accumulation. Renal protection of RGZ from AGEs may be associated with the suppression of PAI-1 expression through PPAR-dependent and independent mechanisms.
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PMID:Rosiglitazone prevents advanced glycation end products-induced renal toxicity likely through suppression of plasminogen activator inhibitor-1. 1726 99

Tenofovir disoproxil fumarate (TDF) is a first-line drug used in patients with highly active retroviral disease; however, it can cause renal failure associated with many tubular anomalies that may be due to down regulation of a variety of ion transporters. Because rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist induces the expression of many of these same transporters, we tested if the nephrotoxicity can be ameliorated by its use. High doses of TDF caused severe renal failure in rats accompanied by a reduction in endothelial nitric-oxide synthase and intense renal vasoconstriction; all of which were significantly improved by rosiglitazone treatment. Low-dose TDF did not alter glomerular filtration rate but produced significant phosphaturia, proximal tubular acidosis, polyuria and a reduced urinary concentrating ability. These alterations were caused by specific downregulation of the sodium-phosphorus cotransporter, sodium/hydrogen exchanger 3 and aquaporin 2. A Fanconi's-like syndrome was ruled out as there was no proteinuria or glycosuria. Rosiglitazone reversed TDF-induced tubular nephrotoxicity, normalized urinary biochemical parameters and membrane transporter protein expression. These studies suggest that rosiglitazone treatment might be useful in patients presenting with TFV-induced nephrotoxicity especially in those with hypophosphatemia or reduced glomerular filtration rate.
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PMID:Rosiglitazone reverses tenofovir-induced nephrotoxicity. 1856 54

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