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)

In the first few hours following immune complex deposition and complement-mediated neutrophil (PMN) infiltration, glomerular generation rates of the arachidonate 5-lipoxygenase (5-LO) derivatives leukotrienes (LT) C4, D4, and B4 are stimulated markedly. These LTs exert effects on glomerular functions which include reduction in the glomerular ultrafiltration coefficient and glomerular filtration rates, exacerbation of proteinuria, and amplification of PMN-provoked glomerular damage through LTB4-induced PMN chemotaxis, adhesion, and activation. Following this early burst, glomerular LT synthesis is suppressed, macrophages replace PMNs, and glomerular generation of 15-S-hydroxyeicosatetraenoic acid [15-(S)-HETE], a 15-lipoxygenase derivative of arachidonic acid and a precursor molecule for lipoxin (LX) biosynthesis, increases progressively over the ensuing days to weeks. Here, we summarize evidence supporting the notion that the activation of the 15-LO pathway in the wake of early 5-LO activity is a specific counter-inflammatory signal which limits and antagonizes the proinflammatory actions of leukotrienes.
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PMID:15-Lipoxygenase products as leukotriene antagonists: therapeutic potential in glomerulonephritis. 140 59

Nephrotoxic nephritis (NTN) is characterized by glomerular inflammation, an increase in glomerular eicosanoid synthesis, and renal dysfunction. Data further suggest that eicosanoids may play a critical role in the inflammatory response. In the current study, we examined the effects of in vivo manipulation of arachidonate metabolism on the cellular component of the inflammatory response in NTN. We found that inhibition of cyclooxygenase with indomethacin in mild NTN caused a two- to fourfold increase in the leukocyte influx into glomeruli with a change histologically from a focal to a more diffuse lesion. Both the accompanying proteinuria and the increase in ex vivo glomerular eicosanoid production were also augmented by the administration of indomethacin. The effect of indomethacin was reversible and not limited to the acute phase of NTN. The administration of aspirin, like indomethacin, augmented the glomerular inflammation of NTN. Neither OKY-046 (a thromboxane synthase inhibitor) nor MK-886 (a 5-lipoxygenase inhibitor) altered the glomerular inflammation of NTN. Administration of exogenous prostaglandin E (in the form of misoprostol) did diminish the proteinuria accompanying NTN; however, glomerular inflammation was not significantly affected. Incubation of glomeruli with [14C]arachidonate demonstrated the presence of noncyclooxygenase pathways of arachidonate metabolism (11-, 12-, and 15-lipoxygenases) with increased activity in NTN. These data demonstrate that cyclooxygenase inhibition may paradoxically worsen glomerular inflammation and suggest a potential role for noncyclooxygenase/non-5-lipoxygenase pathways of arachidonate metabolism.
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PMID:Paradoxical exacerbation of leukocyte-mediated glomerulonephritis with cyclooxygenase inhibition. 151 Jan 21

Leukotriene B4 (LTB4) is the major 5-lipoxgenase product released during early experimental glomerulonephritis. To test its functional relevance, its actions in the normal rat kidney and its influence on renal function in the heterologous phase of mild nephrotoxic serum-induced glomerular injury were examined. Intrarenal administration of leukotriene B4 resulted in mild vasorelaxant and natriuretic responses which were shared by 12(R)-hydroxyeicosatetraenoic acid but not 12(S)-leukotriene B4 or 12(S)-hydroxyeicosatetraenoic acid, suggesting activation of a common recognition site with a requirement for 12(R) stereochemistry. The polymorphonuclear cell-specific activator, N-formyl-Met-Leu-Phe, stimulated leukotriene B4 production from isolated perfused kidneys harvested from nephrotoxic serum-treated rats to a significantly greater degree than from control animals treated with nonimmune rabbit serum. The renal production of leukotriene B4 correlated directly and strongly (r = 0.79, P less than 0.01) with renal myeloperoxidase activity, suggesting interdependence of leukotriene B4 generation and polymorphonuclear cell infiltration. In vivo, intrarenal administration of leukotriene B4 to rats with mild nephrotoxic serum-induced injury was associated with an increase in polymorphonuclear cell infiltration, reduction in renal plasma flow rate, and marked exacerbation of the fall in glomerular filtration rate, the latter correlating strongly with the number of infiltrating polymorphonuclear cells/glomerulus, whereas inhibition of 5-lipoxygenase led to preservation of glomerular filtration rate and abrogation of proteinuria. Thus, although devoid of vasoconstrictor actions in the normal kidney, increased intrarenal generation of leukotriene B4 during early nephrotoxic serum-induced glomerular injury amplifies leukocyte-dependent reductions in glomerular perfusion and filtration rates, likely due to enhancement of polymorphonuclear cell recruitment/activation.
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PMID:Functional significance of leukotriene B4 in normal and glomerulonephritic kidneys. 165 93

The administration of a single-injection of Adriamycin (ADR) to rats results in marked proteinuria and glomerular morphological changes that are similar to minimal change disease in humans. We have hypothesized that Adriamycin, by itself or through the release of some mediators from resident glomerular cells, could provoke a damage to epithelial glomerular cells. Sprague-Dawley rats received a single injection of Adriamycin, 7.5 mg/kg bw, allocated randomly in several groups and treated throughout 2 weeks of follow-up. All control nontreated animals developed important nephrotic syndrome and degenerative lesions of epithelial glomerular cells. Isolated glomeruli from animals injected with adriamycin 14 days before synthesized thromboxane (TxB2) and platelet activating factor (PAF) in amounts above the rates of control glomeruli. Animals treated with three structurally different PAF receptor antagonists did not present proteinuria or only to a very low extent (p less than 0.0005). In these rats no alterations in epithelial cells were noted. Furthermore, no significant changes in the TxB2 production were noted in rats treated with BN 52021, a PAF receptor antagonist. Leukotrienes also seem to participate since treatment with a 5-lipoxygenase inhibitor partially corrected proteinuria. Moreover, glomeruli from animals with nephrosis and treated with this compound presented only a discrete reduction in the PAF synthesis. On the whole, these data suggest a key role for PAF in the pathogenesis of adriamycin nephropathy. Other lipid meditors, released in cascade simultaneously or thereafter, could perpetuate the renal damage.
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PMID:Involvement of lipid mediators in the pathogenesis of experimental nephrosis in rats: its pharmacological modulation. 165 28

A novel series of (3-pyridylmethyl)benzoquinone derivatives was molecular designed and synthesized for the dual purpose of inhibiting thromboxane A2 and leukotriene biosynthesis enzymes and scavenging active oxygen species (AOS). They were evaluated for inhibition of TXA2 synthase, inhibition of 5-lipoxygenase, and for their scavenging activity of AOS using the thiobarbituric acid method. 2,3,5-Trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone (24, CV-6504) was the most promising derivative since it showed efficient AOS scavenging activity (inhibition of lipid peroxidation in rat brain homogenates: IC50 = 1.8 x 10(-6) M) as well as potent, specific, and well-balanced inhibitory effects on both enzymes (inhibitory effect on TXA2 synthase in human blood, IC50 = 3.3 x 10(-7) M; inhibitory effect on 5-lipoxygenase in human blood, IC50 = 3.6 x 10(-7) M). In adriamycin-induced proteinuria in a rat model, compound 24 at 10 mg/kg per day (po) suppressed proteinuria by more than 50%. The proteinuria, however, could not be reduced by single administration of an inhibitor specific for thromboxane A2 synthase [(E)-7-phenyl-7-(3-pyridyl)-6-heptenoic acid (2, CV-4151)] or for 5-lipoxygenase [2-(12-hydroxy-5,10-dodecadiynyl)-3,5,6-trimethyl-1,4-benzoquinone (1, AA-861)]. The proteinuria was also not reduced by administration of an AOS scavenger, 2-O-octadecylascorbic acid (4, CV-3611). Triple function compounds such as compound 24 that specifically inhibit both enzymes as well as scavenge AOS possess a variety of pharmacologically beneficial effects.
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PMID:Dual inhibitors of thromboxane A2 synthase and 5-lipoxygenase with scavenging activity of active oxygen species. Synthesis of a novel series of (3-pyridylmethyl)benzoquinone derivatives. 199 26

Thromboxane A2 (TXA2), leukotrienes (LTs) and free radicals are considered to be possible mediators in the induction of glomerular injury and proteinuria. In this study, we examined the involvement of these three mediators and the protective effect of simultaneous inhibition of all three in puromycin aminonucleoside (PAN) nephrosis in rats. A single intraperitoneal injection of PAN (100 mg/kg) induced massive proteinuria and enhanced production of TXA2 and LTs from arachidonic acid in renal cortical slices and renal glomeruli, and increased malondialdehyde levels in plasma, urine and renal cortex. Oral administration of CV-6504(HCl) (3 to 20 mg/kg/day, for 1 to 2 weeks), a novel treble inhibitor of TXA2 synthetase, 5-lipoxygenase and lipid peroxidation, dose-dependently attenuated PAN-induced proteinuria and the increases in these three mediators. Any single specific inhibitor (CV-4151, a TXA2 synthetase inhibitor; AA-861, a 5-lipoxygenase inhibitor; or CV-3611, a radical scavenger) or a combination of two inhibitors showed no or only a slight antiproteinuric effect, but the combination of all three inhibitors significantly reduced PAN-induced proteinuria. These results suggest that, these three mediators may be involved in the pathogenesis of PAN nephrosis and that CV-6504(HCl), which can simultaneously inhibit all three, may be a useful therapeutic agent for nephrosis.
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PMID:Involvement of thromboxane A2, leukotrienes and free radicals in puromycin nephrosis in rats. 206 8

We examined glomerular synthesis of the 5-lipoxygenase metabolite, LTB4, in normal and immune-injured rat glomeruli. Glomeruli isolated from normal rats and from rats with nephrotoxic serum nephritis (NSN), passive Heymann nephritis (PHN) and cationic bovine gamma globulin (CBGG)-induced glomerulonephritis were incubated with the calcium ionophore A23187 (3 microM). Lipids in the glomeruli and media were extracted with ethyl acetate, and were purified and fractionated by HPLC. Immunoreactive-LTB4 (i-LTB4) was determined by radioimmunoassay on HPLC fractions with a detection limit of 50 pg of i-LTB4. A large peak of i-LTB4 that comigrated with authentic LTB4 was found exclusively in glomeruli isolated from the CBGG-injected rats. Addition of the lipoxygenase inhibitor BW755C (50 micrograms/ml) to glomerular incubation resulted in greater than 90% inhibition of i-LTB4. Synthesis of i-LTB4 by glomeruli from normal, NSN and PHN rats was undetectable. Glomerular LTB4 synthesis by CBGG-injected rats was confirmed by radiometric HPLC and by gas chromatography mass-spectroscopy (GC-MS) analysis. In order to rule out synthesis of LTB4 by neutrophils entrapped in the glomeruli, a group of rats received 1,000 rad total body x irradiation, with shielding of the kidneys before induction of CBGG glomerulonephritis. Despite greater than 95% reduction in total leukocyte count, glomerular synthesis of LTB4 remained enhanced. Augmented glomerular synthesis of the proinflammatory lipid, LTB4, in the CBGG model of glomerular disease could have an important role in the development of glomerular injury and proteinuria.
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PMID:Increased leukotriene B4 synthesis in immune injured rat glomeruli. 283 26

The development of renal dysfunction in experimental glomerulonephritis (GN) is mediated in part by enhanced leukotriene (LT) formation. In our studies the pathophysiological role of LTs was investigated through pharmacological inhibition of LT biosynthesis in a rat model of nephrotoxic serum nephritis. MK-0591, an indirect inhibitor of 5-lipoxygenase activity, was co-administered to rats injected with nephrotoxic rabbit serum, followed by assessment of renal function, morphology and microsomal LTC4 synthase activity on day 7. A significant improvement in glomerular function was noted (p < 0.05), together with a 50% reduction in proteinuria (p < 0.01) in animals receiving MK-0591 (60 mg kg-1 day-1). In addition, the fall in renal LTC4 synthase activity which occurred in nephritic rats (to 74% of control values, p < 0.01) was prevented in drug-treated animals. Based on these results, it appears that inhibition of LT biosynthesis protects against both renal impairment and alterations in LTC4 synthase activity during the development of experimental GN, and may provide a useful therapeutic adjunct in the treatment of this disease.
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PMID:Inhibition of leukotriene biosynthesis improves renal function in experimental glomerulonephritis. 755 79

The gene transcription of 5-lipoxygenase (5-LO) and 5-lipoxygenase-activating protein (FLAP) in renal tissue of patients with IgA nephropathy and mesangial proliferative glomerulonephritis were analyzed by amplification of reverse transcribed mRNA with polymerase chain reaction (PCR). The level of expression was determined by analysis of the PCR products of 5-LO, FLAP, and beta-actin. Forty percent of the patients expressed both 5-LO and FLAP. Relative to beta-actin, FLAP expression (0.42 +/- 0.21) was higher than 5-LO (0.14 +/- 0.10). Comparison of clinical data showed that patients who expressed 5-LO and FLAP had a lower glomerular filtration rate and an increased level of blood urea nitrogen, serum creatinine, and proteinuria. The results suggest arachidonic acid metabolism by inflammatory cells in renal tissue may play an important role in human glomerulonephritis.
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PMID:Expression of 5-lipoxygenase and 5-lipoxygenase activation protein in glomerulonephritis. 846 35

The N-hydroxyurea derivatives 70C ((E)-N-[3-[3- (4-fluorophenoxy)phenyl[-1-(R,S)-methylprop-2-enyl]-N-hydroxyurea) and its (R) 225C and (S) 404C enantiomers, which were being developed as 5-lipoxygenase inhibitors for the treatment of certain allergic and inflammatory conditions, were found to cause severe glomerulonephropathy in the rat. The lesion appeared to be of greater severity in female rats compared with male rats. In addition, 70C and 225C treated animals appeared more severely affected than 404C treated animals. Detailed examination of the lesion in animals dosed with 225C showed that there was a clear relationship between the onset of the lesion and the dose given, i.e. the higher the dose the sooner the lesion developed. The earliest changes detected in the kidney by transmission electron microscopy were noted in the glomeruli, in which the visceral cells appeared enlarged and showed varying degrees of foot process loss. In the more advanced lesion, the degree of foot process loss became more obvious and changes in the kidney tubules were seen by light microscopy. The morphological changes were mirrored by a dose-related increase in water consumption, an increased kidney to body weight ratio and gastrointestinal oedema, suggesting impaired renal function. Shortly after the onset of foot process loss, decreases in the total plasma protein and albumin and increases in the plasma cholesterol, triglycerides, urea and creatinine were recorded. These changes, particularly the foot-process loss, together with increased proteinuria, hypoalbuminaemia, hypercholesterolaemia and lipaemia, are all characteristic of "minimal change nephrotic syndrome". Because of the serious nature of the kidney lesion caused by these N-hydroxyureas in the rat, it was considered that it precluded their development as therapeutic agents for use in man.
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PMID:Nephrotic syndrome associated with N-hydroxyureas, inhibitors of 5-lipoxygenase. 852 44


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