Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P02794 (ferritin)
 17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to explore the pathogenic mechanism of proteinuria in glomerulonephritis, ultrastructural changes of the glomerular basement membrane were investigated in rats with chronic serum sickness induced by repeated intravenous injections of bovine serum albumin (experimental rats). Rats injected with saline served as controls. The animals were sacrificed and examined 13 weeks after treatment, when the mean urinary protein of experimental animals reached 206 mg/24h/100g body weight. Enhanced transcapillary passage of anionic ferritin was observed in experimental rats. Purified glomerular basement membranes of control and experimental rats were examined by electron microscopy after negative staining. The glomerular basement membrane of experimental rats had enlarged pores. The results suggest that an increase in the radius of glomerular pores may be responsible for proteinuria in glomerulonephritis.
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PMID:Changes in the molecular sieve of the glomerular basement membrane of rats with chronic serum sickness. 338 99

Infusion into rats of the polycation hexadimethrine (HDM) leads to onset of massive proteinuria, which recovers when the infusion is stopped. Several lines of evidence indicate that the proteinuria results from binding of HDM to polyanions of the glomerular filter, with neutralization of shielding of their charges. To determine the mechanism of this proteinuria, we measured the glomerular sieving coefficients of anionic and neutral forms of albumin and IgG in control and proteinuric rats. Surprisingly, these studies revealed a marked defect in size dependence, but not in charge dependence, of glomerular permselectivity in hexadimethrine-treated animals, indicating that binding of HDM induces a structural change in the glomerular filter. In vitro studies of binding of tritiated HDM and cationized ferritin to glomerular basement membrane (GBM) indicate that the binding is not dependent on proteoglycans such as heparan sulfate, nor on sialoproteins such as podocalyxin, but is dependent on charged carboxyl groups of GBM.
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PMID:Charged compounds of the glomerular filter and their role in normal and disordered permselectivity. 343 10

The polycation hexadimethrine (HDM) binds to anionic sites in the glomerular basement membrane (GBM) and causes heavy proteinuria when infused in vivo. An in vitro assay of 3H-HDM binding to isolated dog GBM was developed, to permit further analysis of the GBM components binding HDM. 3H-HDM binding to isolated GBM was saturable, reversible in dose-dependent fashion by competing polycations, and inhibited by increasing salt concentration and low pH. The pH dependence of binding suggested that most of the HDM binds to carboxyl groups rather than to the sulfate groups of proteoglycans. Removal of heparan sulfate by heparinase or purified heparatinase had no detectable effect on HDM binding. Treatment of GBM with neuraminidase, hyaluronidase, or chondroitinase reduced binding of HDM by a maximum of 20 to 38%. However, substitution of carboxyl anions with nonionizable glycine methyl ester residues resulted in complete elimination of HDM binding. Parallel results were obtained in studies of glomerular localization of cationized ferritin (CatF), pI 8.5. After carboxyl substitution, GBM did not bind CatF; heparinase-treated GBM bound CatF in a distribution not demonstrably different from normal. Cellulose acetate electrophoresis of glycosaminoglycan fractions prepared from treated GBM confirmed that carboxyl modification did not alter the content or charge of the heparan sulfate of GBM, but heparinase treatment removed at least 90% of heparan sulfate. The results indicate that carboxyl groups are quantitatively more important than heparan sulfate for binding of HDM in vitro. Since HDM causes proteinuria in vivo, carboxyl groups may be important for maintenance of normal permselectivity.
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PMID:Polycation binding to glomerular basement membrane. Effect of biochemical modification. 380 16

We have examined the significance of carbohydrate structure to the transglomerular passage of proteins. Carbohydrate-free (non-glycosylated) ferritin, prepared by Concanavalin-A-sepharose affinity chromatography, was perfused into rat kidneys, and was observed to be restricted from transglomerular transport and to accumulate within the lamina rara interna of the glomerular basement membrane. Visibility of the laminar structure of the glomerular basement membrane was enhanced following perfusion fixation containing tannic acid, permitting the observation of charge dense regions within the basement membrane. Non-enzymatically glucosylated ferritin was not restricted by the lamina rara interna and was observed to penetrate the lamina densa and lamina rara externa. Glucosylated ferritin was observed to be sequestered also by epithelial pinocytic vesicles and to be accumulated within multivesicular bodies. Quantitative measurements using fluorescently labelled ferritins indicated the preferential clearance of glucosylated ferritin from the plasma and preferential appearance of glucosylated ferritin in the urine. The differential transport of glucosylated ferritin was not due to the formation of a cationic protein, as isoelectric focusing established that glucosylation of ferritin results in a more anionic protein. These studies suggest that glucosylation of anionic proteins results in their increased transglomerular permeability. This increased protein permeability could contribute to the proteinuria observed in diabetic microangiopathy.
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PMID:Preferential transport of non-enzymatically glucosylated ferritin across the kidney glomerulus. 383 26

The altered functional properties of the glomerular capillary wall in a model of autologous immune complex disease (Heymann's nephritis) was studied by electron microscopy using intravenously injected protein tracers of varying molecular weight. There was an increase in the permeability of the glomerular basement membrane (GBM) itself to large molecules; this change was focal and was found in those areas where the GBM contained immune complex deposits. Both ferritin and catalase, tracers normally restricted from passing the glomerular filter, were present in the urinary space within minutes of injection. No evidence was obtained for increased glomerular epithelial transport in this disease. Foot process swelling and "close" junction formation was moderate, even in animals with marked degrees of proteinuria. Indirect evidence, therefore, makes an alteration in the slit pore complex likely. In addition, there was immediate and selective concentration of all tracers within deposits, though ferritin was partially excluded from some deposits. This phenomenon may be of significance in the perpetuation of the disease.
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PMID:Altered functional properties of the renal glomerulus in autologous immune complex nephritis: an ultrastructural tracer study. 413 94

To clarify the mechanism of hexadimethrine-induced proteinuria, we studied the changes in stainable glomerular basement membrane anions and renal hemodynamics during hexadimethrine (HDM) infusion. To determine whether glomerular anions were neutralized in vivo, animals infused with HDM received cationized ferritin intravenously, or their kidneys were perfused in situ with lysozyme. During its infusion, HDM bound heavily within the glomerular basement membrane, and binding of the cationic probes was virtually abolished. During recovery after HDM infusion, HDM deposits diminished and the binding of the cationic probes recovered to normal. The inverse correlation between HDM binding and binding of the cationic probes confirms that the glomerular binding of HDM is associated with neutralization or shielding of the glomerular basement membrane anions in vivo. Renal hemodynamic parameters and urinary protein excretion rate were measured before, during, and after infusion of HDM. Heavy proteinuria appeared during HDM infusion and persisted for 1 hour after its discontinuation. Although glomerular filtration rate, renal plasma flow, and urine flow rate decreased transiently at the onset of proteinuria, they returned to baseline levels before resolution of proteinuria. Filtration fraction never changed significantly. Thus, proteinuria cannot be attributed solely to renal hemodynamic factors. These results strengthen our hypothesis that HDM induces proteinuria as a consequence of its binding to and neutralization of glomerular basement membrane fixed anions.
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PMID:Stainable glomerular basement membrane polyanions and renal hemodynamics during hexadimethrine-induced proteinuria. 619 47

We studied the effect of the administration of different doses of antigen in a model of chronic glomerulonephritis produced in mice by the daily injection of apoferritin. Four groups of mice received intraperitoneal injections of 4 mg apoferritin (group 1), 2 mg apoferritin (group 2), 1 mg apoferritin (group 3), or saline (group 4) daily. Significant proteinuria and the presence of antiapoferritin antibody were demonstrated in mice immunized with apoferritin. The severity of histologic damage and the extent of staining for IgG significantly increased with larger doses of apoferritin. Electron microscopy revealed subepithelial and mesangial electron-dense deposits. Administration of large daily doses of apoferritin to mice results in a reliable model of immune complex glomerulonephritis and crescent formation.
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PMID:Chronic serum sickness in the mouse. Relationship of antigen dose to glomerular pathology. 621 78

We investigated the pathogenesis of increased glomerular permeability in Balb/c mice after 5 weeks of administration of a polyclonal B cell activator (bacterial lipopolysaccharide). The glomerular transfer of anionic ferritin across the capillary walls and the urinary excretion of serum albumin served as probes of glomerular permeability; anionic groups of the glomerular basement membrane were assessed by the binding of cationized ferritin, and glomeruli were studied by light, immunofluorescence, and electron microscopy. The mice developed circulating immune complexes, proteinuria, and a proliferative glomerulonephritis, with mesangial and capillary loop deposits of immunoreactants. Increased transfer of anionic ferritin molecules occurred across capillary walls with and without demonstrable electron-dense deposits; detachments of visceral epithelium were not seen, and epithelial transport of anionic ferritin was negligible. Loss of anionic groups was extensive in glomerular capillary loops with and without associated electron-dense deposits. The findings indicate that an increase in glomerular permeability may precede the deposition of immunoreactants in the capillary wall; that filtration of macromolecules can occur across capillary walls with or without demonstrable immune deposits; and that loss of anionic groups of the glomerular basement membrane and enhanced filtration of macromolecules can occur in the absence of focal detachments of the visceral epithelium.
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PMID:Altered glomerular permeability in the early phase of immune complex nephritis. 622 69

Hypertension frequently accompanies chronic glomerulonephritis. Mesangial injury and glomerulosclerosis are common in glomerulonephritis and are often harbingers of progressive glomerular destruction. Thus, in a model of mesangial immune injury we studied the relationship between hypertension, mesangial injury, and glomerulosclerosis. We induced mesangial ferritin-antiferritin immune complex disease (FIC) in Dahl salt-sensitive (S) and salt-resistant (R) rats. S and R rats with FIC were fed chow containing 0.3% NaCl until 14 weeks of age and then switched to 8.0% NaCl chow until 28 weeks of age. Groups of control S and R rats (no FIC) were either fed 0.3% NaCl for 28 weeks or switched to 8.0% NaCl chow at 14 weeks of age. Blood pressure, serum creatinine, urinary protein, and glomerular injury (assessed by semiquantitative morphometric analysis) were determined at 14 and 28 weeks of age. R rats with or without FIC did not develop hypertension; mesangial injury was minimal. At 14 weeks of age, only S FIC rats developed hypertension, proteinuria, significant mesangial expansion and early glomerulosclerosis. At 28 weeks of age, proteinuria, mesangial expansion, and glomerulosclerosis were significantly more severe in hypertensive S rats with FIC than in those without FIC. These studies show that despite a normal salt intake, mesangial injury hastened the onset of hypertension, but only in rats genetically predisposed to hypertension (S FIC at 14 weeks). High dietary salt further aggravated hypertension, which, in turn, magnified both mesangial injury and glomerulosclerosis. Clinically, the different rates of progression of human glomerulonephritis associated with hypertension may be in part dependent on similar mechanisms.
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PMID:Mesangial immune injury, hypertension, and progressive glomerular damage in Dahl rats. 623 58

Immunologic mechanisms of proteinuria and ultrastructural alterations of the slit pore complex and glomerular charge barrier were investigated in Munich Wistar (MW) rats with nephrotoxic serum nephritis. Prior to disease induction, normal MW sera demonstrated 50% of the complement hemolytic activity compared with sera obtained from Sprague-Dawley rats. MW rats were sacrificed prior to, at onset (5 to 6 hours), and during maximal proteinuria (heterologous phase). Immunofluorescence revealed binding of rabbit antirat IgG antibodies in a linear pattern to the glomerular basement membrane (GBM) within 15 minutes postinjection. Complement deposition was not demonstrable in vivo in this model. Immediately after injection of nephrotoxic serum a decreased penetration of the GBM occurred, restricting ferritin to the level of the endothelium in in situ fixed glomeruli. GBM permeability to native ferritin did not increase despite areas of epithelial cell detachment, endothelial cell sloughing, and proteinuria between 2 and 24 hours postnephrotoxic serum injection. Colloidal iron initially decreased staining intensity between 6 and 8 hours, with a major decrease at 24 hours, indicating a loss in glomerular sialoprotein coincident with the onset of proteinuria. Polyethyleneimine (PEI) localization revealed an initial loss of anionic binding sites by 2 hours postinjection. At 6 hours peripheral capillary loops demonstrated only scattered, random polyethyleneimine-binding sites. Splitting of the lamina densa occurred at 24 hours with the exposure of previously undetected anionic binding sites within the lamina densa. Ultrastructurally, as early as 2 hours postnephrotoxic serum injection tissue perfused with tannic acid-glutaraldehyde showed epithelial membranes forming numerous pinocytotic vesicles. Blunting and retraction of foot processes caused displacement and stacking of slit diaphragms prior to the onset of proteinuria. Between 6 and 24 hours postinjection, slit diaphragms appeared to stretch and contract to compensate for epithelial cell retraction. Tangential sections showed neither alterations nor condensation products disrupting the isoporous substructure of the slit diaphragm 24 hours postnephrotoxic serum injection. Polymorphonuclear leukocytes were not found within capillary loops during the heterologous phase of nephrotoxic serum nephritis in MW rats. The absence of complement and polymorphonuclear leukocytes accompanying anti-GBM antibody deposition suggests that early epithelial cell injury and GBM charge alterations in MW rats are mediated by heterologous antibody via a complement-independent mechanism. The lower complement hemolytic activity in normal MW sera may explain the lack of complement involvement in renal lesions in this model of nephrotoxic serum nephritis. Loss of characteristic staining for both glomerular sialoprotein and discrete anionic sites in the GBM coincided with early epithelial cell alterations and occurred prior to the onset of measurable proteinuria.
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PMID:Complement-independent nephrotoxic serum nephritis in Munich Wistar rats. Immunologic and ultrastructural studies. 634 11


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