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)

Platelet-activating factor (PAF) has been suggested recently to play an important role in immune glomerulonephritis, favoring the formation of immune deposits in glomeruli and contributing to the local inflammatory reaction. Here we sought to investigate whether urinary PAF excretion was modified in New Zealand Black x New Zealand White mice a model of genetically determined immune complex disease which mimics systemic lupus in humans and whether changes in PAF urinary excretion values correlated with the extent of proteinuria. To clarify the possible "in vivo" relevance of these findings we evaluated whether PAF receptor antagonist has any influence on the evolution of renal disease and survival of these mice. Our results showed that: 1) in lupus mice urinary PAF excretion increased progressively with age in New Zealand Black x White; 2) the increase in PAF excretion correlated with the severity of proteinuria; and 3) the chronic administration of a PAF receptor antagonist [L-659,989 [(+/- )-trans-2-(3-methoxy-5-methylsulfonyl-4-propoxyphenyl)-5- (3,4,5-trimethoxyphenyl)tetrahydrofuran]] starting from 26 weeks of age significantly delayed the onset of proteinuria and prolonged survival.
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PMID:Platelet-activating factor receptor blocking reduces proteinuria and improves survival in lupus autoimmune mice. 165 Aug 36

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

The effect of platelet-activating factor (PAF) on glomerular permeability to macromolecules was investigated in the isolated kidneys from normal male Sprague-Dawley rats perfused at constant pressure. Compared with basal values, infusion of PAF (10 nM final concentration) into the isolated kidneys induced a progressive and significant increase in protein excretion (6.7 +/- 2.7 vs. 40.7 +/- 10.4 micrograms/min, P less than 0.01), completely reversible 20 min after PAF infusion was discontinued (8.5 +/- 1.3 micrograms/min). In additional experiments, during PAF infusion the fractional clearance of small neutral dextrans (radius 24-48 A), defined as the ratio of the clearance of neutral dextrans to the clearance of creatinine, was comparable to preinfusion values, whereas fractional clearance of large dextrans (greater than 50 A) was significantly elevated (P less than 0.005) above preinfusion values. The specific PAF receptor antagonist L 652731 completely prevented the increased fractional clearance of large dextrans induced by PAF. Finally, lowering Ca2+ concentration in the perfusion medium from 2.5 to less than 0.1 mM markedly reduced proteinuria in isolated kidneys exposed to PAF (80.0 +/- 10.3, 42.8 +/- 3.1, and 22.0 +/- 7.6 micrograms/min, respectively, for 2.5, 1.25, and less than 0.1 mM). These results indicate that in isolated perfused kidneys 1) PAF-induced proteinuria is a functional phenomenon reversible on discontinuing PAF infusion, 2) PAF modifies glomerular size-selective properties by increasing transmural passage of large dextran molecules, and 3) PAF-induced change in glomerular permselective properties is dependent on Ca2+ concentration in the extracellular medium.
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PMID:Platelet-activating factor alters glomerular barrier size selectivity for macromolecules in rats. 171 21

Platelet-activating factor (PAF) is a potent autacoid that participates in inflammation and other pathophysiological processes. In this review we deal with recent evidence suggesting that PAF is a mediator that is released early during glomerular injury. PAF can be synthesized in the glomerulus by infiltrating intrinsic glomerular cells. Normal glomeruli produce PAF upon stimulation, and glomerular PAF synthesis is increased in a variety of experimental glomerulopathies. The local infusion of PAF into the renal artery of isolated blood-free kidneys induces proteinuria. PAF attracts and activates inflammatory cells. Glomerular mesangial, endothelial and epithelial cells are also targets for PAF. Therapy with specific PAF receptor antagonists has prevented or reduced proteinuria and improved glomerular inflammation in several experimental models of proliferative glomerulonephritis and minimal change nephrosis. However, the beneficial effect of administration of PAF antagonists once proteinuria is fully developed has been minimal. PAF may also play a role in the recruitment of inflammatory interstitial cells.
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PMID:The role of platelet-activating factor (PAF) in experimental glomerular injury. 181 22

Untreated 16-week-old MRL/MpJ-lpr/lpr (lpr) mice, when compared to congenic MRL/MpJ-+/+ (+/+) mice, are characterized by a systemic lupus erythematosus syndrome, including severe glomerulonephritis, proteinuria and reduction of renal function. We hypothesized that platelet activating factor (PAF), a potent chemotactic and proinflammatory phospholipid mediator synthesized and released by circulating cells, glomerular mesangial and renal medullary interstitial cells, may play a role in the development of renal injury in lupus mice. We assessed renal PAF synthesis in lpr as well as +/+ mice and the effect of treatment with a PAF receptor blocking agent. Treatment with the PAF receptor antagonist L659,989 for four weeks, starting at 12 weeks of age, significantly reduced acute glomerular infiltration and proliferation, and prevented chronic glomerular histological changes; proteinuria and serum creatinine levels were also significantly reduced in treated mice. Renal PAF production was increased in lpr when compared to +/+ mice, and treatment with L659,989 restored renal PAF synthesis to the control levels. Our results support the hypothesis that PAF can be one of the mediators of glomerular injury characteristic of murine lupus nephritis, and indicate the possible therapeutic utility of PAF receptor antagonists in immunologic renal diseases.
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PMID:Platelet activating factor receptor blockade ameliorates murine systemic lupus erythematosus. 196 46

Platelet-activating factor (PAF) has been implicated as a potential mediator in renal immune injury, but little is known on the mechanisms by which this endogenous phospholipid could contribute to the development of glomerular proteinuria that occurs during immunologically mediated inflammatory reactions. Several experimental models of renal immune injury, including hyperacute kidney allograft rejection, acute serum sickness and nephrotoxic nephritis, and human studies have clearly indicated that renal damage is associated with increased intraglomerular formation of PAF. However, a definitive proof of its pathophysiologic role has been obtained only by pharmacological inhibition of PAF activity at receptor level. In this context we have documented that the PAF receptor antagonist L-652,731 markedly prevented renal function deterioration and development of proteinuria, and reduced glomerular hypercellularity, fibrin deposition in Bowman's space, and tubular cast formation in a rabbit model of nephrotoxic serum nephritis. Concerning the mechanisms by which PAF may induce proteinuria, it has been suggested that PAF increases glomerular permeability to proteins through the release of cationic proteins from platelets and polymorphonuclear neutrophils infiltrating the glomerular tuft, and their deposition in the glomerular capillary wall with loss of fixed anionic charges. We have recently shown that in isolated rat kidney preparations perfused with a cell-free medium, the addition of PAF, but not its vehicle or 2-lyso-PAF, to the perfusate caused a progressive increase in urinary protein excretion. PAF-induced proteinuria was prevented by exposure of isolated kidneys to the PAF receptor antagonist L-652,731.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of platelet-activating factor in renal immune injury and proteinuria. 225 82

Previous studies have shown that platelet-activating factor (PAF) receptor blocking has a protective effect on rabbit nephrotoxic nephritis (NTN). We examined whether arachidonic acid (AA) metabolism is altered in NTN and whether a PAF receptor antagonist has any influence on such changes. Rabbits injected with anti-glomerular basement membrane antiserum in the heterologous phase had a markedly increased glomerular thromboxane B2 (TxB2) production level, whereas no changes have been detected in glomerular 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and prostaglandin E2 (PGE2). During the autologous phase of the disease, the glomerular TxB2 level was even higher than in the heterologous phase. The level of 6-keto-PGF1 alpha was significantly lower than normal, and the level of PGE2 was unchanged in respect to the basal values. The use of L-652,731 (a specific PAF receptor antagonist) reversed the abnormal generation of AA metabolites at glomerular level both in the heterologous and autologous phase of the disease. The effect of L-652,731 on AA metabolism is likely to be an indirect result of the PAF receptor blocking, because L-652,731 given to normal rabbits had no direct effect on glomerular AA metabolism. To assess whether the beneficial effect of L-652,731 in NTN is at least in part mediated by its capability of suppressing the excessive intrarenal synthesis of thromboxane A2 (TxA2), we compared the effect of L-652,731 with that of a selective TxA2-synthase inhibitor (FCE-22178). FCE-22178 ameliorated the morphologic expression of rabbit NTN and reduced function deterioration. The protective effect of L-652,731 on proteinuria in the autologous phase and on glomerular filtration rate in both phases was superior to that of FCE-22178. We conclude that an excessive intraglomerular synthesis of TxA2 occurs in rabbit NTN that can play a role in renal function deterioration. Both a specific PAF receptor antagonist and a TxA2-synthase inhibitor reduced the exaggerated TxA2 synthesis and favorably influenced the evolution of the disease.
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PMID:Enhanced glomerular thromboxane A2 mediates some pathophysiologic effect of platelet-activating factor in rabbit nephrotoxic nephritis: evidence from biochemical measurements and inhibitor trials. 254 Dec 12

Release of acetyl glyceryl ether phosphorylcholine, platelet-activating factor (PAF), has been demonstrated to be associated with glomerular inflammatory damage in acute serum sickness. Moreover, PAF can increase glomerular permeability to proteins and induce mesangial contraction. Thus PAF might be a good candidate as a mediator of glomerular damage. However the in vivo evidence that PAF might cause glomerular injury is lacking. To evaluate if PAF has a major role in promoting glomerular inflammatory reaction and fibrin deposition, we studied the effect of a molecule, L-652,731, which blocks the PAF receptor, on the evolution of an experimental model of anti-glomerular basement membrane (anti-GBM) glomerulonephritis (GN). GN was initiated by sheep-anti-rabbit nephrotoxic serum. A proliferative GN regularly occurred in which heavy proteinuria, intra and extracapillary proliferation of resident and inflammatory cells and fibrin deposition in Bowman's capsule were the prominent findings. Our results showed that the PAF receptor antagonist reduces the glomerular damage in anti-GBM GN, supporting the hypothesis that PAF is indeed a mediator of glomerular inflammatory reaction. PAF receptor blocking prevented renal function deterioration in the early phase of the disease, probably preserving glomerular hemodynamics. In the delayed phase of the disease the PAF receptor antagonist reduced proteinuria and prevented renal function deterioration and fibrin deposition. These effects appear to be mediated by an inhibitory action of PAF receptor blocking on macrophage accumulation and activation.
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PMID:Platelet activating factor (PAF) as a mediator of injury in nephrotoxic nephritis. 303 32

Platelet-activating factor (PAF) is a lipid mediator of inflammation believed to play a role in glomerulonephritis by favoring immune complex formation and modulating the subsequent inflammatory reaction. Some evidence indicates that PAF may also be one of the mediators of proteinuria. Previous work suggested that PAF can increase glomerular permeability to proteins, activating platelets and inflammatory cells to release cationic proteins. In the present study, we addressed the possibility that PAF might directly increase glomerular permeability to proteins independently of platelets and inflammatory cells. We used a preparation of isolated rat kidney perfused with an artificial cell-free medium. After stabilization and two 10-minute control clearance periods, kidneys perfused in a closed circuit were exposed to PAF (2 nM or 10 nM final concentration) or 2-lyso-PAF (10 nM final concentration) or vehicle for 40 minutes. Glomerular filtration rate, measured as creatinine clearance, and renal vascular resistance did not significantly change when either PAF (2 nM or 10 nM) or 2-lyso-PAF, or vehicle were added to the perfusion fluid. Unlike vehicle or 2-lyso-PAF, addition of PAF at the final concentration of 2 and 10 nM to the perfusate produced a dose-dependent progressive increase in urinary protein excretion. PAF-induced proteinuria was prevented by L-652,731, a specific PAF receptor antagonist, suggesting that PAF's effect on glomerular permeability to proteins is likely to be related to its biologic activity. Several pharmacologic manipulations addressed to the potential mediators of PAF effect on glomerular permeability to proteins would exclude that the effect of PAF on isolated perfused kidney is mediated by cyclooxygenase or lipoxygenase products, or is the result of oxygen-free radical generation. The possibility that PAF enhances glomerular permeability to proteins by changing the glomerular barrier electrostatic properties was explored using polyethylene-imine. Electron microscopy examination revealed no difference in the distribution of electron-dense deposits along the glomerular basement membrane in kidneys exposed to 10 nM PAF or vehicle.
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PMID:Effect of platelet-activating factor and its specific receptor antagonist on glomerular permeability to proteins in isolated perfused rat kidney. 312 98

Platelet-activating factor (PAF) is a potent inflammatory mediator that participates in the pathogenesis of proteinuria and glomerular damage. However, the role of this lipid in glomerular sclerosis remains unknown. This study examines the effect of PAF on the regulation of extracellular matrix proteins by rat and human mesangial cells. PAF increased in a dose-dependent manner the gene expression of fibronectin and type IV collagen, but not type I collagen. Moreover, an increase in cell-associated and soluble fibronectin synthesis was also seen. These effects were abolished by BN52021 and WEB2086, two different PAF receptor antagonists. Because transforming growth factor (TGF)-beta has been considered a profibrogenic cytokine, this study also evaluated whether PAF effects might be mediated by the production of endogenous TGF-beta. PAF caused an increase in TGF-beta1 mRNA expression (by a protein kinase C-dependent pathway) and TGF-beta activity. Moreover, PAF-induced fibronectin synthesis was totally abolished when an anti-TGF-beta-neutralizing antibody was added to the culture medium, suggesting that PAF stimulates fibronectin synthesis, at least in part, through the induction of TGF-beta. Addition of cycloheximide, a protein synthesis inhibitor, upregulated PAF-induced fibronectin mRNA expression but downregulated PAF-induced TGF-beta1 gene expression, suggesting the existence of different regulatory transcriptional factors of the two proteins. These results suggest that PAF may be implicated in matrix accumulation during renal injury and therefore contribute to the pathogenesis of glomerulosclerosis.
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PMID:Platelet-activating factor stimulates gene expression and synthesis of matrix proteins in cultured rat and human mesangial cells: role of TGF-beta. 925 53


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