Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.2.1.17 (lysozyme)
21,489 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Renal clearance is a major pathway for regulating the levels of insulin and other low molecular weight polypeptide hormones in the systemic circulation. Previous studies have shown that the reabsorption of insulin from the glomerular filtrate occurs by binding to as yet unidentified sites on the luminal surface of proximal tubule cells followed by endocytosis and degradation in lysosomes. In this study, an insulin binding site was identified in renal microvillar membranes by chemical cross-linking procedures. By immunoprecipitation it was demonstrated that this binding site is megalin, the large multiligand binding endocytic receptor that is abundantly expressed in clathrin-coated pits on the apical surface of proximal tubule cells. Moreover, using cytochemical procedures, it was also shown that megalin is able to internalize insulin into endocytic vesicles. In ligand blotting assays, megalin also bound several other low molecular weight polypeptides, including beta2-microglobulin, epidermal growth factor, prolactin, lysozyme, and cytochrome c. These data suggest that megalin may play a significant role as a renal reabsorption receptor for the uptake of insulin and other low molecular weight polypeptides from the glomerular filtrate.
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PMID:Megalin is an endocytic receptor for insulin. 977 76

Plasma retinol-binding protein (RBP) combined with vitamin A (retinol) is partially filtered through the glomerulus and then absorbed by proximal tubule cells, leading to recycling of retinol to the circulation. Recently, it was shown that reabsorption of RBP-retinol complexes by proximal tubule cells is mediated by megalin (gp 330), an apical endocytic receptor. It was proposed that RBP is transported by megalin to lysosomes, where it is degraded, thus liberating retinol, which then combines with newly synthesized RBP to be secreted into the bloodstream. This study shows that passage of RBP through immortalized rat renal proximal tubule (IRPT) cells occurs by transcytosis after megalin-mediated endocytosis, which provides an alternative pathway for recycling of retinol. IRPT cells cultured as polarized monolayers with tight junctions were used on permeable filters in the upper chamber of dual-chambered devices, with megalin expression exclusively on the upper surface. After addition of RBP to the upper chamber and incubation at 37 degrees C, intact RBP was found in fluids that were collected from the lower chamber. In contrast, control substances (mannitol, lysozyme, albumin, and glutathione-S-transferase) were not appreciably transported across IRPT cells, indicating that passage of RBP was by transcytosis and not by paracellular leakage. Confocal microscopy analysis of IRPT cells after addition of RBP to the upper chamber revealed RBP-containing granules at the apical membrane, subapically, and also at basolateral membranes. When RBP was added to IRPT cells together with megalin competitors, the amount of transcytosed RBP was markedly reduced. We also found that some RBP was internalized and degraded by IRPT cells, but this process was not appreciably affected by megalin competitors, indicating that RBP endocytosed by megalin was not transported to lysosomes and degraded but rather transcytosed across IRPT cells.
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PMID:Transcytosis of retinol-binding protein across renal proximal tubule cells after megalin (gp 330)-mediated endocytosis. 1127 24

To investigate the pharmacokinetic interaction between substrates of megalin, a 600-kDa endocytic receptor abundantly expressed in the renal proximal tubules, we examined the effect of gentamicin infusion on the pharmacokinetics of fluorescein isothiocyanate (FITC)-lysozyme in rats. Infusion of gentamicin did not affect the plasma concentration-time profile of FITC-lysozyme. On the other hand, gentamicin significantly decreased the accumulation of FITC-lysozyme in the renal cortex and medulla, whereas the accumulation in the renal papilla, liver, brain and lung was not changed. Urinary excretion of FITC-lysozyme was increased by gentamicin, whereas there was no change in the biliary excretion of FITC-lysozyme or its degradation products. Gentamicin infusion had little influence on the ATP content in the renal cortex and urinary excretion of glucose, indicating that nephrotoxicity is not induced by short-term infusion of gentamicin. These findings suggest that lysozyme and gentamicin interact with each other in their reabsorption processes in the renal proximal tubules, probably by competing for their binding to megalin expressed in the apical membrane of the renal proximal tubules.
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PMID:Effect of gentamicin on pharmacokinetics of lysozyme in rats: interaction between megalin substrates in the kidney. 1249 51

Absorption of fluorescein isothiocyanate-labeled lysozyme (FITC-lysozyme) was examined in rat small intestine. Messenger RNA of megalin, an endocytic receptor for lysozyme in the kidney, was expressed in the lower but not in the upper intestine. In in situ closed loop and recirculation methods, absorption of FITC-lysozyme from the upper intestine was much higher than from the lower intestine. The absorption rate of FITC-lysozyme in the upper intestine was significantly higher than FITC-dextran and was inhibited by unlabeled lysozyme in a concentration-dependent manner. The absorption of FITC-lysozyme was also inhibited by spermine and phenylarsine oxide. These results indicate that the intestinal absorption of lysozyme is segment-selective and occurs preferentially from the upper intestine. Megalin expressed in the lower intestine appears not to have a significant role in the absorption of lysozyme. In the upper intestine, lysozyme appears to be absorbed by an endocytic pathway, and cationic charge may be important for lysozyme absorption.
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PMID:Segment-selective absorption of lysozyme in the intestine. 1546 1

The mechanism of protein reabsorption in the kidney of lower vertebrates remains insufficiently investigated in spite of raising interest to the amphibian and fish kidneys as a useful model for physiological and pathophysiological examinations. In the present study, we examined the renal tubular uptake and the internalization rote of lysozyme after its intravenous injection in the wintering frog Rana temporaria using immunohisto- and immunocytochemistry and specific markers for some endocytic compartments. The distinct expression of megalin and cubilin in the proximal tubule cells of lysozyme-injected frogs was revealed whereas kidney tissue of control animals showed no positive immunoreactivity. Lysozyme was detected in the apical endocytic compartment of the tubular cells and colocalized with clathrin 10 min after injection. After 20 min, lysozyme was located in the subapical compartment negative to clathrin (endosomes), and intracellular trafficking of lysozyme was coincided with the distribution of megalin and cubilin. However, internalized protein was retained in the endosomes and did not reach lysosomes within 30 min after treatment that may indicate the inhibition of intracellular trafficking in hibernating frogs. For the first time, we provided the evidence that lysozyme is filtered through the glomeruli and absorbed by receptor-mediated clathrin-dependent endocytosis in the frog proximal tubule cells. Thus, the protein uptake in the amphibian mesonephros is mediated by megalin and cubilin that confirms a critical role of endocytic receptors in the renal reabsorption of proteins in amphibians as in mammals.
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PMID:Receptor-mediated endocytosis of lysozyme in renal proximal tubules of the frog Rana temporaria. 2615 Jan 56

Effective delivery of drug carriers selectively to the kidney is challenging because of their uptake by the reticuloendothelial system in the liver and spleen, which limits effective treatment of kidney diseases and results in side effects. To address this issue, we synthesized l-serine (Ser)-modified polyamidoamine dendrimer (PAMAM) as a potent renal targeting drug carrier. Approximately 82% of the dose was accumulated in the kidney at 3 h after i.v. injection of ¹¹¹In-labeled Ser-PAMAM in mice, while i.v. injection of ¹¹¹In-labeled unmodified PAMAM, l-threonine modified PAMAM, and l-tyrosine modified PAMAM resulted in kidney accumulations of 28%, 35%, and 31%, respectively. Single-photon emission computed tomography/computed tomography (SPECT/CT) images also indicated that ¹¹¹In-labeled Ser-PAMAM specifically accumulated in the kidneys. An intrakidney distribution study showed that fluorescein isothiocyanate-labeled Ser-PAMAM accumulated predominantly in renal proximal tubules. Results of a cellular uptake study of Ser-PAMAM in LLC-PK1 cells in the presence of inhibitors [genistein, 5-(N-ethyl-N-isopropyl)amiloride, and lysozyme] revealed that caveolae-mediated endocytosis, micropinocytosis, and megalin were associated with the renal accumulation of Ser-PAMAM. The efficient renal distribution and angiotensin-converting enzyme (ACE) inhibition effect of captopril (CAP), an ACE inhibitor, was observed after i.v. injection of the Ser-PAMAM-CAP conjugate. These findings indicate that Ser-PAMAM is a promising renal targeting drug carrier for the treatment of kidney diseases. Thus, the results of this study demonstrate efficient renal targeting of a drug carrier via Ser modification.
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PMID:l-Serine-modified polyamidoamine dendrimer as a highly potent renal targeting drug carrier. 3024 62

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