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)

Puromycin aminonucleoside (PA) and Adriamycin (ADR) cause glomerular proteinuria associated with degenerative alterations of glomerular visceral epithelial cells (GVEC) and detachment from the glomerular basement membrane when administered to rats. This in vitro study was performed to define, in detail, the quantitative and qualitative changes of a number of adhesion-associated proteins (cytoskeletal, extracellular matrix and integrin proteins) upon exposure to PA and ADR. By immunofluorescence we observed: (1) dose- and incubation-time-dependent filament pattern changes and decreased staining of the cytoskeletal proteins actin, vimentin, keratin, and beta-tubulin; (2) an altered distribution, and decreased expression of the extracellular matrix proteins laminin and heparan sulfate and (3) a loss of the beta 1-integrin focal adhesions upon exposure to PA and ADR. Using an ELISA, a concentration-dependent decrease was found (a 50% reduction with 50 micrograms/ml PA for 48 h and with 2 micrograms/ml ADR for 24 h) in the production of cytoskeletal and extracellular matrix proteins per cell. These general effects were suggestive of a disturbance of protein synthesis but, by metabolic labelling studies, no reduction in overall protein synthesis was found. Using two-dimensional PAGE on 35S-methionine steady-state labeled cells, no changes were found in intracellular protein patterns of PA- and ADR-treated cells (pH 5-7.5, MW 110-20 kD). We hypothesize that exposure of GVEC in vitro to PA and ADR might result, directly or indirectly, in perturbation of the macromolecular organization of cytoskeletal and extracellular matrix proteins with loss of GVEC adhesion.
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PMID:Puromycin aminonucleoside and adriamycin disturb cytoskeletal and extracellular matrix protein organization, but not protein synthesis of cultured glomerular epithelial cells. 808 96

Puromycin aminonucleoside--(PAN) treated rats develop acute nephrotic syndrome, mimicking human minimal lesion disease. In PAN nephrosis, podocyte detachment from the glomerular basement membrane (GBM) is the most likely cause of massive proteinuria in this model. To elucidate further the mechanisms of PAN-induced cellular dysfunction, new methods were employed to visualize podocyte cytoskeletal aggregation and to measure fibrillar attachment to the GBM. Adult Sprague-Dawley rats (n = 4/group) received a single tail-vein injection of PAN (75 mg/kg). On days 1, 2, 3, and 5 following injection, 24-hour urine collections were obtained for creatinine clearance, albuminuria, and total proteinuria. Then kidneys from each group were fixed by perfusion. Podocytic cytoskeleton was visualized by scanning electron microscopy. Subepithelial GBM staining and attachment fiber number, observed on digitized images of transmission electron micrographs, were quantitated with computer-based density analysis. A significant reduction in attachment fiber number in the GBM lamina rara externa occurred by day 5. On scanning electron micrographs, the secondary and tertiary podocytic processes were observed to be formed by highly aggregated cytoskeleton, which became partially disaggregated by day 3, was totally absent by day 5, and normalized by day 20. Immunogold staining revealed that actin and vinculin localized to the tertiary podocytic processes in the normal state were dispersed into the cell body following PAN. Podocyte cytoskeletal disaggregation precedes, and detachment from the GBM occurs simultaneously with, the onset of massive proteinuria in the PAN model.
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PMID:Podocytic cytoskeletal disaggregation and basement-membrane detachment in puromycin aminonucleoside nephrosis. 849 56

Puromycin aminonucleoside nephrosis (PAN) is a model for human minimal change nephropathy induced in rats by injection of puromycin. In PAN, defective sialylation of a major sialoprotein of podocytes, podocalyxin, has been demonstrated and the consequent decrease of anionic charge suggested as a causative factor for increased glomerular permeability and proteinuria. Whether defective sialylation is a general feature of PAN affecting also glomerular glycosphingolipids is not known. We have shown that rat glomeruli are rich in disialogangliosides GD3 and O-acetyl GD3, the functions of which are not known. Here, we made a sequential analysis of the glomerular gangliosides, especially of GD3 and its O-acetyl derivative in acute PAN using immunohistochemical and biochemical techniques and compared the results with another rat model of glomerular disease, Heymann nephritis. The prominent immunohistochemical finding was the almost total disappearance of glomerular O-acetyl GD3 and a substantial decrease of its precursor GD3 peaking at 10 days after injection of puromycin. Segmental areas lacking these gangliosides remained in glomeruli still at 30 days after injection. The response was dose dependent. Semiquantitative analysis by thin layer chromatograms showed that O-acetyl GD3 was decreased by 41% already at 3 days and by 60% at 10 days after injection of puromycin. Also GD3, the immediate precursor of O-acetyl GD3, was decreased by 20 and 19%, respectively, at 3 and 10 days after injection. At 3 days after injection, overt proteinuria had not started. At these times, no other changes were observed in the glomerular gangliosides. The decrease of glomerular GD3 and O-acetyl GD3 indicates a decrease of GD3 synthase activity and perhaps of O-acetyltransferase activity in PAN nephrosis. As these changes preceded the overt proteinuria, they may have a causal relationship to it. In the glomeruli of Heymann nephritic rats, no similar changes were seen, suggesting that the sialylation defect is not due to proteinuria but is a consequence of targeted puromycin action on cells.
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PMID:Decrease of glomerular disialogangliosides in puromycin nephrosis of the rat. 878 Apr 4

Puromycin aminonucleoside nephrosis (PAN), a rat model of human minimal change nephropathy, is characterized by extensive flattening of glomerular epithelial cell (podocyte) foot processes and by severe proteinuria. For comparison of expression of glomerular membrane proteins of normal and PAN rats, a membrane protein fraction of isolated rat glomeruli was prepared and monoclonal antibodies were raised against it. An IgG-secreting clone designated LF3 was selected that specifically immunolabeled podocytes of normal but not of PAN rats. The antigen of LF3 IgG was identified as a 43-kd glycoprotein. Molecular cloning of its cDNA was performed in a delta gt11 expression library prepared from mRNA of isolated rat glomeruli. The predicted amino acid sequence indicated a 166-amino-acid integral membrane protein with a single membrane-spanning domain, two potential phosphorylation sites in its short cytoplasmic tail, and six potential O-glycosylation sites in the large ectodomain. High amino acid sequence identities were found to membrane glycoproteins of rat lung and bone and mouse thymus epithelial cells as well as to a phorbol-ester-induced protein in a mouse osteoblast cell line and to a canine influenza C virus receptor. In PAN, expression of this 43-kd protein was selectively reduced to < 30%, as determined by quantitative immunogold electron microscopy, immunoblotting, and Northern blotting. These data provide evidence that transcription of the 43-kd transmembrane podocyte glycoprotein is specifically down-regulated in PAN. To indicate that this protein could be associated with transformation of arborized foot processes to flat feet (Latin, pes planus) we have called it podoplanin.
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PMID:Podoplanin, novel 43-kd membrane protein of glomerular epithelial cells, is down-regulated in puromycin nephrosis. 932 48

The urinary excretion of total protein, low-MW proteins, albumin, high-MW proteins, and intact IgG was measured in male Wistar rats between the ages of 5-52 weeks, and in rats with experimentally induced glomerular or tubular proteinuria. About 25% of aging rats spontaneously developed focal glomerulosclerosis and a mild glomerular proteinuria. By age 52 weeks, total protein excretion in rats with glomerulosclerosis exceeded that of unaffected rats by a factor of seven (39.5 vs 5.4 mg/24 hr x 100 g body wt), and albumin excretion was seven times higher than IgG excretion in affected rats (21.2 vs 2.9 mg/24 hr x 100 g body wt). Rats with chromate toxicity exhibited a reversible tubular proteinuria, with low-molecular weight protein excretion reaching 16.8 mg/24 hr x 100 g body wt (75% of total protein excretion) at the time of peak toxicity. IgG excretion remained less than 0.6 mg/24 hr x 100 g body wt. Aminonucleoside induced a massive but reversible glomerular proteinuria (204 mg/24 hr x 100 g body wt), with IgG excretion reaching 11.4 mg/24 hr x 100 g body wt (6% of total protein excretion) at the time of peak toxicity. Biochemical and immunochemical studies showed that, while some intact IgG is present in normal rat urine, most IgG immunoreactivity is derived from low-molecular weight catabolic fragments of IgG which interfere with the immunoassay of intact urinary IgG. One of these fragments, probably Fc fragment, may be involved in the pathogenesis of focal segmental glomerulosclerosis.
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PMID:The renal handling of IgG in the aging rat and in experimental kidney disease. 940 48

Puromycin aminonucleoside (PAN) has been known to induce proteinuria. The increased generation of reactive oxygen species (ROS) has been implicated in this toxicity of PAN. We have reported that PAN increases the synthesis of methylguanidine (MG) and creatol which are the products of the reaction of creatinine and the hydroxyl radical in isolated rat hepatocytes. However, the mechanism for the increased ROS induced by PAN is still unclear. In this paper, we investigate the role of protein kinase C (PKC) on the PAN induced reactive oxygen generation in isolated rat hepatocytes. Isolated hepatocytes were incubated in Krebs-Henseleit bicarbonate buffer containing 3% BSA, 16.6 mM creatinine and tested reagents. MG and creatol were determined by high-performance liquid chromatography using 9,10-phenanthrenequinone for the post-labeling. PAN increased MG and creatol synthesis in isolated rat hepatocytes by 60%. 1-(5-Isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7), a PKC inhibitor, at 10 and 100 microM significantly inhibited MG and creatol synthesis with or without PAN. The inhibition rate is dose dependent from 10 to 100 microM. H1004, a reagent used as control for H-7, did not affect (at 10 microM) or increased little (at 100 microM) the synthesis of MG and creatol. Ro31-8425, a potent PKC inhibitor, significantly inhibited (at 10 microM) MG synthesis in the presence of PAN. PKC in the membrane fraction, a marker of PKC activation, increased over the initial concentration by a factor of 1.65-fold at 60 min incubation and 2.16-fold at 120 min with PAN, while it changed little without PAN. These results indicate that PAN activates PKC resulting in increased hydroxyl radical generation in isolated rat hepatocytes.
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PMID:The role of protein kinase C in the increased generation in isolated rat hepatocytes of the hydroxyl radical by puromycin aminonucleoside. 1079 14

Puromycin aminonucleoside (PAN) administration in rats produces an experimental model of nephrotic syndrome characterized by glomerular epithelial cell injury and proteinuria. The purpose of this study was to examine the role of nitric oxide (NO) in this model of minimal change glomerular disease. Aminoguanidine (AG) was used to inhibit inducible nitric oxide synthase (iNOS). Sprague-Dawley rats were divided into Control (N = 9), PAN (N = 14), AG (N = 2), and PAN + AG (N = 12) treatment groups. Control animals received saline (i.v. ), PAN animals received PAN (75 mg/kg, i.v.), and PAN + AG animals received PAN plus AG (50 mg/kg, i.p., twice daily). AG animals received a saline injection (i.v.) on day 0 in the place of PAN and then AG on the same schedule as the PAN + AG group. Animals were kept in metabolic cages, and urinary protein excretion and nitrite (NO(2)(-)) excretion were measured daily. PAN administration increased urinary NO(2)(-) excretion by day 2, and levels remained elevated through day 7. AG prevented this PAN-induced increase in urinary NO(2)(-) excretion. Plasma nitrate (NO(3)(-)) and NO(2)(-) (NOx) concentrations were also increased in the PAN and PAN + AG groups. iNOS protein expression was not detected in either the glomeruli or the cortex at day 7. Proteinuria developed in PAN animals on day 4 and increased steadily through day 7. PAN + AG animals showed a pattern similar to that of the PAN group. These results indicated that in contrast to models of proliferative glomerulonephritis, NO formation during PAN-induced nephrotic syndrome is increased but does not participate in the development of glomerular injury as measured by proteinuria.
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PMID:Lack of a role for inducible nitric oxide synthase in an experimental model of nephrotic syndrome. 1080 55

Glomerular epithelial protein 1 (GLEPP1) is a podocyte receptor membrane protein tyrosine phosphatase located on the apical cell membrane of visceral glomerular epithelial cell and foot processes. This receptor plays a role in regulating the structure and function of podocyte foot process. To better understand the utility of GLEPP1 as a marker of glomerular injury, the amount and distribution of GLEPP1 protein and mRNA were examined by immunohistochemistry, Western blot and RNase protection assay in a model of podocyte injury in the rat. Puromycin aminonucleoside nephrosis was induced by single intraperitoneal injection of puromycin aminonucleoside (PAN, 20 mg/100g BW). Tissues were analyzed at 0, 5, 7, 11, 21, 45, 80 and 126 days after PAN injection so as to include both the acute phase of proteinuria associated with foot process effacement (days 5-11) and the chronic phase of proteinuria associated with glomerulosclerosis (days 45-126). At day 5, GLEPP1 protein and mRNA were reduced from the normal range (265.2 +/- 79.6 x 10(6) moles/glomerulus and 100%) to 15% of normal (41.8 +/- 4.8 x 10(6) moles/glomerulus, p < 0.005). This occurred in association with an increase in urinary protein content from 1.8 +/- 1 to 99.0 +/- 61 mg/day (p < 0.001). In contrast, podocalyxin did not change significantly at this time. By day 11, GLEPP1 protein and mRNA had begun to return towards baseline. By day 45-126, at a time when glomerular scarring was present, GLEPP1 was absent from glomerulosclerotic areas although the total glomerular content of GLEPP1 was not different from normal. We conclude that GLEPP1 expression, unlike podocalyxin, reflects podocyte injury induced by PAN. GLEPP1 expression may be a useful marker of podocyte injury.
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PMID:GLEPP1 receptor tyrosine phosphatase (Ptpro) in rat PAN nephrosis. A marker of acute podocyte injury. 1196 7

1 Puromycin aminonucleoside (PAN)-induced nephrosis is a model of human minimal change disease. In rats, PAN induces nephrotic-range proteinuria, renal epithelial cell (podocyte) damage, infiltration of mononuclear leukocytes, and apoptosis of several renal cell types. 2 Retinoic acid (RA) modulates a wide range of biological processes, such as inflammation and apoptosis. Since renal damage by PAN is characterized by inflammatory infiltration and epithelial cell death, the effect of treatment with all-trans RA (tRA) was examined in the PAN nephrosis model and in the cultured differentiated podocyte. 3 Treatment with tRA 4 days after PAN injection did not inhibit the proteinuria peak but reversed it significantly. However, treatment with tRA both before and 2 days after the injection of PAN protected the glomerular epithelial cells, diminishing the cellular edema and diffuseness of the foot process effacement. Preservation of the podocyte architecture correlated with the inhibition of proteinuria. The anti-inflammatory effect of tRA was evidenced by the inhibition of PAN-induced interstitial mononuclear cell infiltration and the decreased renal expression of two molecules involved in monocyte infiltration: fibronectin and monocyte chemoattractant protein-1. TUNEL assays showed that tRA inhibited the PAN-induced apoptosis of cultured differentiated mouse podocytes. 4 We conclude that tRA treatment may prevent proteinuria by protecting the podocytes from injury and diminishing the interstitial mononuclear infiltrate in the model of PAN nephrosis. Retinoids are a potential new treatment for kidney diseases characterized by proteinuria and mononuclear cell infiltration.
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PMID:Retinoids as a potential treatment for experimental puromycin-induced nephrosis. 1281 6

Podocyte foot process effacement and disruption of the slit diaphragm are typically associated with glomerular proteinuria and can be induced in rats by the injection of puromycin aminonucleoside. Here, we show that the induction of puromycin aminonucleoside nephrosis involves podocyte migration conducted by a coordinated interplay between the cysteine protease cathepsin L and alpha(3) integrin. Puromycin aminonucleoside treatment up-regulates cathepsin L expression in podocytes in vivo as well as expression and enzymatic activity of cathepsin L in podocytes in vitro. Isolated podocytes from mice lacking cathepsin L are protected from cell puromycin aminonucleoside-induced cell detachment. The functional significance of cathepsin L expression was underscored by the observation that puromycin aminonucleoside-induced cell migration was slowed down in cathepsin L-deficient podocytes and by the preservation of cell-cell contacts and expression of vital slit diaphragm protein CD2AP. Cathepsin L expression and activity were induced in podocytes lacking alpha(3) integrin. Similarly, acute functional inhibition of alpha(3) integrin in wild type podocytes with a blocking antibody increased the expression of cathepsin L activity. Down-regulation of alpha(3) integrin protected against puromycin aminonucleoside-induced podocyte detachment. In summary, these data establish that podocyte foot process effacement is a migratory event involving a novel interplay between cathepsin L and alpha(3) integrin.
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PMID:Podocyte migration during nephrotic syndrome requires a coordinated interplay between cathepsin L and alpha3 integrin. 1519 81


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