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

IgA nephropathy is one of the most common forms of glomerular disease. Nearly 25% of affected patients progress to end-stage renal disease over a 20-25-y follow-up period. IgA-containing immune complexes stimulate oxygen-free radical production by mesangial cells in vitro. The excessive oxidant stress may mediate glomerular injury in this disorder. Therefore, we studied whether dietary supplementation with the antioxidant agent, vitamin E, attenuates renal disease in an experimental model of incipient IgA nephropathy with mild kidney inflammation. IgA nephropathy was induced in male Lewis rats by oral immunization with 0.1% bovine gamma-globulin (BGG)-containing drinking water for 8 wk. At the completion of this period, animals received BGG, 1 mg/dose i.v., on three successive days. Experimental rats (n = 10) received a specially formulated diet containing 100 IU of vitamin E/kg of chow, whereas control animals (n = 10) were fed chow containing 30 IU of vitamin/kg of chow. The BGG immunization regimen induced mesangial IgA deposition in all rats. Vitamin E supplementation resulted in a nearly 5-fold increase in the serum vitamin E concentration. Vitamin E-treated rats gained more weight and had a lower incidence of hematuria, 20% versus 80% (p < 0.03). Moreover, proteinuria was decreased by 50%, and reduced renal plasma flow was restored to normal, compared with untreated rats with IgA nephropathy. Glomerular hypertrophy occurred in animals with IgA nephropathy, but less so in those receiving vitamin E supplementation. Renal cortical malondialdehyde content was reduced from 1.55 +/- 0.10 to 1.22 +/- 0.09 nmol/mg of protein (p < 0.01) in rats fed the vitamin E-enriched diet. Finally, renal transforming growth factor-beta 1 gene expression was reduced by 34% in rats with IgA nephropathy receiving vitamin E treatment (p < 0.05). We conclude that experimental IgA nephropathy is associated with increased renal oxidant injury. Dietary treatment with the antioxidant agent, vitamin E, attenuated renal functional and structural changes in this experimental glomerulopathy. These studies support the importance of clinical trials for the evaluation of the efficacy of antioxidant therapy in patients with IgA nephropathy.
 ...
PMID:Vitamin E ameliorates renal injury in an experimental model of immunoglobulin A nephropathy. 888 93

The analysis and reassembly of the single steps in the pathogenesis of Heymann nephritis is reasonable well advanced, but still far from being comprehensive. It is established that antibodies against certain epitopes of the megalin/gp330 molecule or RAP are responsible for the formation of glomerular immune deposits. Apparently a second antibody antigen system targeting lipid antigens causes the activation of C5b-9, which triggers the biosynthesis of oxygen-radical-producing enzymes within glomerular epithelial cells. The oxygen radicals cause lipid peroxidation which, by virtue of its toxic products, causes cross-linking of type IV collagen via its NC1 domains. It is possible that this is associated with a distortion and increase of permeability of the glomerular basement membrane, thus causing proteinuria.
 ...
PMID:[Molecular pathogenesis of experimental membraneous glomerulonephritis (Heymann nephritis)]. 892 92

Previous studies have indicated that reactive oxygen species play a key role in puromycin aminonucleoside (PAN)-induced proteinuria in the acute nephrotic phase, and glomerular infiltration of macrophages (M phi) in the acute phase has a critical impact on the subsequent progression to glomerular sclerosis. In the present study, we examined the effect of deferoxamine (DFO), which is known to inhibit the generation of hydroxyl radical on the proteinuria, renal function and morphological changes in PAN-induced chronic glomerulopathy. Rats given a single dose of PAN (150 mg/kg BW, i.p.) were not treated (Group 1, n = 12) or treated with DFO (Group 2 and 3). In Group 2 rats (n = 12), 30 mg of DFO was given for 12 weeks after PAN injection (every day for the first 2 weeks, 3 times a week for the following 2 weeks, once a week for the last 8 weeks). In Group 3 rats (n = 14), DFO was given in an identical manner with Group 2 until 2nd week and was discontinued thereafter. 24-hour urinary protein excretion (UprV) was measured at 1st, 2nd, 4th, 8th, 12th, and 24th weeks. The percentage of segmentally sclerosed glomeruli (%SS), creatinine clearance (Ccr), and serum malondialdehyde levels (MDA) were determined at the 24th week. The average number of M phi per glomerulus (# M phi) was determined at the 4th, 8th and 24th weeks after PAN injection, by biopsy and autopsy. Compared to Group 1 rats, Group 2 rats had a significantly lower amount of UprV throughout the period with marked attenuation in %SS and Ccr. In contrast, UprV in Group 3 was comparable to that in Group 1 except for the 2nd week, and there was no significant difference in %SS or Ccr between Group 1 and 3. Of note, # M phi at 4th week, which significantly correlated with %SS, substantially decreased in Group 2 compared to Group 1 or Group 3 (p < 0.05). These data suggest that the oxidant stress persisting from the acute to the chronic phase of PAN nephropathy plays an important role in inducing glomerular sclerosis. The prevention of progressive glomerular sclerosis following DFO therapy might be associated with an improvement in early glomerular in filtration of M phi.
 ...
PMID:[A role for reactive oxygen species in the pathogenesis of focal glomerulosclerosis]. 895 2

The molecular pathogenesis of human membranous nephropathy (MN) is unknown, despite the relatively high incidence and severity of this glomerular immune disease. Heymann nephritis (HN) in rats is considered an instructive experimental model of MN. This study summarizes current molecular aspects of two key events common to both MN and HN, i.e., formation of characteristic subepithelial immune deposits in the glomerular basement membrane (GBM), and development of glomerular capillary wall damage resulting in proteinuria. In HN, the antigenic targets of immune deposit-forming antibodies were identified in cell membranes of glomerular epithelial cells as a 515-kd glycoprotein (megalin, or gp330), which is a polyspecific receptor related to the low-density lipoprotein receptor family, and an associated 44-kd protein (receptor associated protein, RAP). One epitope was recently narrowed to 14 amino acids in RAP, and several others on megalin/gp330 are under investigation. Proteinuria requires formation of the complement C5b-9 membrane attack complex, which is presumably triggered by antibodies directed against lipid antigens that associate with immune deposit-forming megalin/gp330 immune complexes. Sublytic C5b-9 attack on glomerular epithelial cells causes upregulation of expression of the NADPH oxidoreductase enzyme complex by glomerular cells, which is translocated to their cell surfaces, similar to activated neutrophil granulocytes in the respiratory burst reaction. Subsequently, reactive oxygen species (ROS) are produced locally, which reach the GBM matrix. Here formation of lipid peroxidation (LPO) adducts is found, preferentially on monomeric and dimerized NCl domains of covalently crosslinked Type IV collagen. These structural changes within the GBM could be of functional relevance because treatment with the potent LPO-antagonist probucol reduces proteinuria by < 80%. Intact or fragmented apoprotein E-containing lipoproteins were identified as potential sources of the polyunsaturated lipids required for the production of LPO adducts. Lipoproteins accumulate within immune deposits and show signs of oxidative damage, similar to oxidized LDL within atherosclerotic lesions. Collectively, the results obtained so far in HN permit the compilation of a sequence of events, linking formation of immune deposits with proteinuria. However, despite this relatively detailed knowledge of pathogenic events in HN, the bridge to human NM remains to be built.
 ...
PMID:Molecular mechanisms of glomerular injury in rat experimental membranous nephropathy (Heymann nephritis) 898 29

We evaluated the roles of reactive oxygen species and intrinsic antioxidant enzymes in the development of daunomycin (DM)-induced nephropathy in mice. A single dose of DM (20 mg/kg intravenously) induced proteinuria by day 7 and the nephrotic syndrome by day 14 in DM-sensitive strain (A/J) but not in DM-resistant strain (C57BL/6J) (B6). Renal cortical lipid peroxide levels in the A/J mice significantly increased at days 2, 4, and 7 after DM injection, whereas no increase was observed in the B6 mice. The resistance to DM in B6 mice was associated with higher activities in renal cortical superoxide dismutase and glutathione peroxidase. The administration of superoxide dismutase or of dimethylthiourea significantly suppressed the DM-induced proteinuria in the A/J mice. Four days of superoxide dismutase or dimethylthiourea administration suppressed the proteinuria. These findings suggested that murine DM-nephropathy appeared to be mediated by reactive oxygen species and that intrinsic antioxidant enzyme activities may play an important role in the susceptibility to DM-induced nephropathy in mice.
 ...
PMID:Roles of reactive oxygen species and antioxidant enzymes in murine daunomycin-induced nephropathy. 901 94

Heymann nephritis is an extensively studied experimental model of human membranous nephropathy, a currently barely treatable glomerular immune disease. Several basic concepts were discovered by the study of this experiment disease, such as in situ formation of immune deposits, and the roles of the complement system and of oxygen radicals in the development of proteinuria. The major goal of our studies is to develop specific therapies for the experimental and eventually also for the human disease, based on the detailed knowledge of the molecular pathogenic mechanisms. The target of immune deposit forming antibodies was identified as a large membrane glycoprotein with structural similarities with the LDL-receptor. This protein serves as polyspecific receptor, and its intriguing properties in different organs have developed into a separate area of research. Sofar the precise amino acid sequences of several epitopes for the nephritogenic antibodies were identified, thus offering the unique possibility to develop precisely targeted specific therapeutic strategies. Here we link the mechanisms of immune deposit formation with the development of proteinuria.
 ...
PMID:[Molecular analysis of experimental membranous glomerulonephritis (Heymann nephritis)]. 906 96

Reactive oxygen species (ROS) are produced and released into the extracellular spaces in numerous diseases and contribute to development and progression, for example, of inflammatory diseases, proteinuria, and tumor invasion. However, little is known about ROS-induced chemical changes of interstitial matrix proteins and their consequences for the integrity of the matrix meshwork. As basement membranes and other matrices are highly cross-linked and complex, the relatively simple matrix produced by Engelbreth-Holm-Swarm (EHS) sarcoma, and proteins isolated therefrom, were incubated in vitro with defined concentrations of ROS that were generated by the Fenton or xanthine oxidase/xanthine reactions. This resulted in two counter-current effects. Although up to approximately 15% of the EHS matrix proteins were released into the supernatant in a ROS dose-response relationship, the residual insoluble matrix was partially cross-linked by ROS. Matrix proteins released into the supernatants were examined by rotary shadowing, quantitative sodium dodecyl sulfate polyacrylamide gel electrophoresis, immunoblotting, and fluorospectrometry for loss of tryptophans and formation of bityrosine residues. At relatively low ROS concentrations, selective liberation of morphologically intact laminin/entactin was found that, however, failed to reassociate and showed oxidative damage of its tryptophan residues. At higher ROS concentrations, laminin and entactin were progressively disintegrated, partially fragmented, and eventually completely degraded. At this point oligomers of type IV collagen predominated in the supernatant, and proteoglycans were not encountered at any concentration of ROS. Similar gradual molecular changes were also obtained when fractions of isolated soluble EHS matrix proteins were incubated with graded concentrations of ROS. In these experiments, the formation of covalently linked oligomers and aggregates paralleled the ROS-dependent formation of cross-linking bityrosine groups. ROS scavengers pinpointed to the hydroxyl radical as the most damaging radical species. Protease inhibitor experiments suggested that degradation of matrix proteins was caused primarily by the direct action of ROS and not by proteolysis by potentially contaminating proteases. Collectively, these results provide evidence that EHS matrix proteins show differential sensitivity to ROS-induced damage in a reproducible, sequential pattern, in the order entactin > laminin > type IV collagen, and that ROS cause partial dissociation and cross-linking of the EHS matrix.
 ...
PMID:Reactive oxygen species cause direct damage of Engelbreth-Holm-Swarm matrix. 921 47

The purpose of this study was to determine the effect of the hemoglobin based oxygen carrier, polyethylene glycol conjugated bovine hemoglobin (PEG-Hb) on the physiology of the rat. This study was divided into the following 3 parts: pharmacokinetics, cardiovascular, and histopathology. Pharmacokinetic studies evaluated the PEG-Hb circulatory life and the resultant effect on urine composition. Telemetric intravascular blood pressure probes monitored the heart rate and mean arterial pressure. Renal arterial blood flow was determined by intraoperative perivascular ultrasound. Tissue histology was evaluated for both time and model dependent responses. The mean circulatory half-life of PEG-Hb was 17.7+/-0.3 h. Proteinuria and hemoglobinuria were greatly reduced with PEG conjugation. PEG-Hb treated rats produced 8.5 times and 49 times less proteinuria and hemoglobinuria, respectively, than unmodified bovine Hb treated animals. The mean arterial pressure (MAP) in PEG-Hb treated rats was insignificantly different from sham controls undergoing a 30% exchange transfusion while dextran caused an initial reduction and bovine Hb produced a prolonged elevation in the MAP. In these same anesthetized rats, PEG-Hb slightly decreased the heart rate while dextran caused an increase and bovine Hb had no effect. In addition, PEG-Hb was able to maintain the renal arterial blood flow while both Ringer's lactate and bovine Hb caused a reduction in the blood flow. Finally, PEG-Hb treated rats showed a dose and time dependent formation of vacuoles within the renal proximal convoluted tubules and splenic macrophages in both top-load and exchange transfusion models, but no other morphological changes. In conclusion, PEG-Hb had a relatively long vascular persistence that did not cause any significant alterations in the urinalysis, cardiovascular function, or tissue histopathology in the rat.
 ...
PMID:Effect of polyethylene glycol conjugated bovine hemoglobin in both top-load and exchange transfusion rat models. 933 63

Results from several radical scavenger studies indirectly suggested an involvement of reactive oxygen species in the pathogenesis of puromycin aminonucleoside glomerulopathy. In this study, generation of reactive oxygen species was examined directly in glomeruli isolated from rats in the acute phase of puromycin aminonucleoside nephrosis and related to the changes in the glomerular antioxidant defense. Five and nine days after puromycin aminonucleoside injection, gross proteinuria, reduced creatinine clearances, and typical changes of glomerular morphology were present. Levels of reactive oxygen species were increased eightfold in glomeruli isolated 15 min after puromycin aminonucleoside injection, returned to baseline levels on days 1 and 5 after injection, and rose again to 14-fold on day 9 after injection, as determined by chemiluminescence with luminol. Further analysis of increased glomerular radical generation, using the chemiluminescence enhancer lucigenin and different radical scavengers, suggested a predominant involvement of hydroxyl radical and hydrogen peroxide in the initial increase in reactive oxygen species 15 min after puromycin aminonucleoside. Nine days after induction of nephrosis, primarily superoxide anion and hydroxyl radical were found to contribute to increased reactive oxygen species. Despite oxidative stress, antioxidant enzymes were not induced in the course of nephrosis. On the contrary, catalase and glutathione peroxidase activities declined 9 d after puromycin aminonucleoside injection. The results indicate that a transient increase in glomerular reactive oxygen species is sufficient to induce the oxidative glomerular injury observed in this model and that the glomerulus may not necessarily respond to oxidative stress with an induction of antioxidant enzymes.
 ...
PMID:Reactive oxygen species and antioxidant defense in puromycin aminonucleoside glomerulopathy. 935 75

Lipoprotein(a) [Lp(a)] may be elevated in patients with the nephrotic syndrome and patients on hemodialysis or continuous ambulatory peritoneal dialysis. High levels of Lp(a) are due to proteinuria or an activated acute-phase response. Serum concentrations greater than 30 mg/dl are independently associated with coronary heart disease. Data from cell culture studies suggest that it is not uptake of Lp(a) by mesangial cells but trapping by matrix proteins that contributes to the generation of glomerular apo(a) deposits. Lp(a) alters mesangial cell DNA synthesis and stimulates the generation of reactive oxygen species. Prolonged exposure to Lp(a) causes mesangial cell death in vitro culture' experiments. Lp(a) does not alter autocrine transforming growth factor-beta transcription in human mesangial cells and has, unlike low-density lipoprotein, no effect on the production of the extracellular matrix protein fibronectin. Future cell culture studies on the role of Lp(a) in renal disease have to address whether Lp(a) induces cell death via apoptosis and to what extent the generation of oxygen radicals is involved in this process.
 ...
PMID:Lipoprotein(a) in nephrotic syndrome and end-stage renal disease. 938 8


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>