UMLS:C0033687 - FACTA Search

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Query: UMLS:C0033687 (proteinuria)
24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Attachment of podocytes to the glomerular basement membrane is thought to be mediated primarily by alpha 3/beta 1-integrins and by cytoskeletal proteins including actin, talin, vinculin, and alpha-actinin. We analyzed the expression of those molecules in rat glomeruli at several time points during induction of podocyte foot process effacement and nephrotic syndrome with puromycin aminonucleoside (PAN). PAN injection resulted in marked induction of glomerular alpha-actinin (40% increase vs. paired controls, P < 0.01), which clearly preceded development of podocyte foot process effacement and proteinuria and localized almost exclusively to podocytes. Delayed induction of glomerular alpha 3-integrin (44% increase vs. paired controls, P < 0.01) following foot process effacement was also observed but was not restricted to podocytes. No significant changes in glomerular vinculin, talin, beta 1-integrin, or total actin expression occurred at any time point during disease development. We conclude that foot process effacement is preceded by induction of alpha-actinin in podocytes in experimental nephrotic syndrome. Altered expression of this actin cross-linking protein in podocytes may have a pathogenic role in foot process effacement in nephrotic syndrome.
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PMID:Podocyte alpha-actinin induction precedes foot process effacement in experimental nephrotic syndrome. 924 3

An interaction between angiotensin (Ang) II and transforming growth factor (TGF)-beta 1 is gaining increasing recognition. Ang II has been implicated in the progression of renal disease, and TGF-beta 1 is a potent fibrosis-promoting cytokine. We sought to determine whether the beneficial effects of renin-angiotensin system blockade on remnant kidney function were associated with a reduction in renal TGF-beta 1 in this model of chronic renal failure. After subtotal renal ablation, rats fed a 40% protein diet and treated with losartan not only had a reduction in systolic BP (96 +/- 8 versus 130 +/- 8 mmHg, P < 0.05, losartan versus control) and urinary protein excretion (4 +/- 5 versus 23 +/- 20 g/d, P < 0.05, losartan versus control), but also exhibited a reduction in renal TGF-beta 1 mRNA (194 +/- 64 versus 411 +/- 101 optical density units, P < 0.05, losartan versus control) and TGF-beta 1 protein levels (9.8 +/- 2.5 versus 18.6 +/- 5.8 ng/g of renal tissue, P < 0.05, losartan versus control). The elevation of TGF-beta 1 in the remnant kidney was most pronounced in the scar region (22.9 +/- 13.1 versus 5.8 +/- 3.7 ng/g, P < 0.05, scar versus nonscar). A combination of reserpine, hydralazine, and hydrochlorothiazide, although effective in lowering systemic BP in this model of chronic renal failure, was not associated with a reduction in proteinuria or TGF-beta 1. We conclude that in this model of progressive renal injury, Ang II antagonism may exert a beneficial effect in part by its negative influence on TGF-beta 1.
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PMID:Interaction of angiotensin II and TGF-beta 1 in the rat remnant kidney. 935 76

Whenever there is heavy proteinuria, the glomerular epithelial cells, the podocytes, show dramatic morphological changes which clearly demonstrate changes in cell adhesion. However, there is little information on the types of cell adhesion molecules expressed in the normal human glomerulus. Assessments of changes in cell adhesion molecules in human proteinuria have been confined to semi-quantitative immunostaining for integrins, and the results have not been entirely consistent. This study sought first to define which cell adhesion molecules are present in the normal glomerulus, using indirect immunofluorescence and a panel of antibodies directed against transmembrane adhesion proteins and against several cytoplasmic proteins which are known to be involved in adhesion. A wide variety of integrins were detected, the dominant form being alpha 3 beta 1. The cytoplasmic focal adhesion proteins vinculin, talin, paxillin, p130CAS, and pp125FAK were detected, although vinculin appeared to be confined mainly to the mesangium. The only intercellular adhesion molecule detected in the vicinity of the slit diaphragm was ZO-1; the results imply that the slit diaphragm does not bear a close relationship to any other form of intercellular junction. Changes in these adhesion components were also studied in proteinuria, using 18 cases each of minimal change nephropathy, 'early' membranous nephropathy, and normal controls. Fluorescence intensity was measured by image capture using a low light video camera and subsequent digital image analysis, an approach which demonstrated acceptable reproducibility. The most striking changes were an increase in phosphotyrosine and p130CAS in the nephrotic patients. Contrary to previous reports, little change was found in the expression of the most abundant integrins, nor did overall glomerular staining for ZO-1 alter. These results imply a controlled alteration in glomerular cell adhesion in nephrotic states in man, probable representing increased turnover of cell adhesion structures rather than the decrease which has been reported in short-term animal models. This is the first report of increased glomerular phosphotyrosine in man, which is associated with less stable adhesions and may be related to the loss of foot processes. Using human biopsy material, it was not possible to determine which proteins were phosphorylated, but the probable relationships to changes in cytoskeletal structure and slit diaphragm permeability justify further study.
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PMID:A quantitative immunofluorescence study of glomerular cell adhesion proteins in proteinuric states. 942 81

Oxidative stress and the fibrogenic cytokine transforming growth factor beta 1 (TGF beta 1) have been implicated in the pathogenesis and progression of IgA nephropathy. In the present study, we used alpha-tocopherol as a dietary supplement to test the hypothesis that the proteinuria, oxidative stress, and TGF beta mRNA can be more effectively lowered with higher doses of alpha-tocopherol. Hematuria, proteinuria, and mesangial IgA deposition are parameters which characterize IgA nephropathy. IgA nephropathy was induced by bovine gamma globulin oral immunization in rats during an 8-week course, and all hallmarks of IgA nephropathy were produced in this 8-week animal model. The elevation in renal malondialdehyde content and TGF beta 1 mRNA, as well as the severity of proteinuria, was blunted by alpha-tocopherol. Our data suggested that conventional dosage of alpha-tocopherol at 100 IU/kg chow lowered kidney TGF beta 1 to control values and increasing the dose by 2 1/2-fold or even 5-fold resulted in no further reduction in TGF beta 1 mRNA. Significant reduction of proteinuria was achieved better with a dose of 250 IU/kg chow of alpha-tocopherol supplementation than with the 100 IU/kg chow. We conclude that alpha-tocopherol at this dose is efficacious in controlling proteinuria, downregulating TGF beta 1, and reducing oxidative stress in experimental IgA nephropathy. Doubling this dose achieved no further benefits.
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PMID:alpha-Tocopherol reduces proteinuria, oxidative stress, and expression of transforming growth factor beta 1 in IgA nephropathy in the rat. 960 45

The alpha 1 beta 1 integrin (VLA-1) is a major collagen/laminin receptor that regulates fibroblast proliferation and mesangial cell migration and cell contraction. We have examined the effect of an antibody to VLA-1 in crescentic glomerulonephritis. Nephrotoxic nephritis was induced in Wistar-Kyoto rats and rats were given monoclonal antibody to VLA-1 (Ha31/8), 2.5 mg/kg, on alternate days. Antibodies were given from day -1 to day 10 or from day 14 to day 28. Treatment from day -1 to day 10, during the early inflammatory phase of nephrotoxic nephritis, had no effect on albuminuria or glomerular crescent formation. In the delayed treatment experiment, all rats developed florid crescentic glomerulonephritis, and control rats showed marked glomerular and tubulointerstitial scarring at day 32. VLA-1 expression, by immunohistochemistry, was increased in glomeruli and around tubules. Proteinuria did not differ between groups. In anti-VLA-1-treated rats, serum creatinine was significantly lower at day 32 (P = 0.002) and renal survival was significantly better (P = 0.045). Both glomerular and interstitial scarring were significantly less at day 32 in rats given anti-VLA-1 (P = 0.002). Deposition of ED(A) fibronectin, a marker of new matrix synthesis, and of type IV collagen, were reduced in glomeruli and interstitium in anti-VLA-1-treated animals (P = 0.0006). Expression of alpha-smooth muscle actin, a marker of myofibroblasts, showed no significant difference. Expression of matrix metalloproteinase-9 was increased in the glomeruli of rats treated with anti-VLA-1. We conclude that VLA-1 mediates both glomerular and interstitial fibrosis in crescentic glomerulonephritis and that neutralization of VLA-1, which enhanced expression of matrix metalloproteinase-9, is a possible therapeutic strategy in progressive renal scarring.
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PMID:Treatment with an antibody to VLA-1 integrin reduces glomerular and tubulointerstitial scarring in a rat model of crescentic glomerulonephritis. 1236

Inhibitors of angiotensin-converting enzyme (ACE) or beta isoforms of protein kinase C (PKC) are nephroprotective in diabetes mellitus. We investigated the influence of streptozotocin (STZ)-induced diabetes mellitus and of treatment with the ACE inhibitor lisinopril (4 mg/kg p.o. twice daily for 4 weeks) on the expression of PKC beta 1 and PKC beta 2 in the renal cortex of female Sprague-Dawley rats. Immunohistochemistry indicated an enhanced renocortical accumulation of macrophages expressing both MHC II, a marker for antigen-presenting cells, as well as PKC beta 2 in STZ diabetes which was confirmed by Western blotting demonstrating an enhanced renocortical expression of MHC II (1.8-fold) as well as of membrane-associated PKC beta 2 (1.9-fold). Whereas immunohistochemistry could not detect unequivocal alterations, Western blotting showed a rise in the renocortical expression of membrane-associated PKC beta 1 (1.7-fold) in STZ diabetes. Lisinopril lowered renocortical albumin content and proteinuria in STZ diabetes and attenuated the enhanced accumulation of macrophages expressing PKC beta 2 as well as the increase of membrane-associated expression of PKC beta 1 and PKC beta 2 in the renal cortex. The data suggest that the nephroprotective actions of the ACE inhibitor lisinopril in experimental diabetes mellitus were associated with and thus could be mediated in part by inhibition of diabetes-induced activation of PKC beta isoenzymes in the renal cortex.
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PMID:Protein kinase C beta isoenzymes in diabetic kidneys and their relation to nephroprotective actions of the ACE inhibitor lisinopril. 1243 80

A number of studies have demonstrated that the urinary ion activity product (IAP) of calcium oxalate (CaOx), as an index of urinary CaOx supersaturation (SS), is higher in renal stone formers than in normal subjects. Besides, the relation between CaOx SS and lithogenesis, crystal CaOx exposition can produce tubular cell as well as renal interstitial lesions. The aim of our study was to evaluate the possible relationship between CaOx SS and tubulointerstitial (TI) damage in an animal model of hyperoxaluria. During four weeks, male Sprague-Dawley rats received: G1 (n = 8) control regular water, and G2 (n = 8) 1% ethylene glycol (ETG) (precursor for oxalates) in drinking water. In order to evaluate urinary CaOx SS, IAP assessed by Tisselius formula was performed. At the end of the study, renal lesions were evaluated by light microscopy and immunohistochemistry. Animals from G2 (ETG) presented higher (p < 0.01) values of: a) urinary oxalate excretion; b) urinary CaOx SS; c) crystalluria score; d) proteinuria; and lower (p < 0.01) creatinine clearance, with respect to the control group (G1). Moreover, pathology studies showed that rats from G2 (ETG), presented significant TI lesions characterized by a higher (p < 0.01) score of: a) tubular atrophy; inflammatory infiltrates (monocyte/macrophage); c) crystal deposits; d) intersticial fibrosis; e) interstitial alpha-smooth muscle actin; f) collagen type III; g) TI TGF beta 1 compared with G1 (control). Rats from G2 (ETG) presented a high correlation between urinary CaOx SS and most of the TI damage parameters evaluated, in especial with interstitial fibrosis. Both, inflammatory infiltrates and urinary CaOx SS were the most significant variables related to interstitial fibrosis. Finally, since hyperoxaluric animals showed higher urinary CaOx SS associated with higher renal TI damage, the results from this study suggest the presence of a tight link between urinary CaOx SS and renal TI damage. Considering these findings we think that urinary CaOx SS control rises in importance beyond nephrolithiasis.
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PMID:[Urinary calcium oxalate supersaturation beyond nephrolithiasis. Relationship with tubulointerstitial damage]. 1279 76

Preclinical and phase I/II studies gave the proof of principle of enzyme replacement therapy (ERT) with recombinant alpha-galactosidase A through the demonstration of the clearance of the accumulated subtrate from plasma and tissues. In a multicenter, randomized, placebo-controlled, double-blind phase Ill study, the biological efficacy of recombinant alpha-galactosidose A (agalsidase beta 1 mg/kg/714 days) was demonstrated on the basis of complete clearance of accumulated globotriaosylceramide from the endothelia of the kidney, heart and skin. The phase III extension study data gives additional results: kidney function appears to be stabilized after 54 to 60 months of treatment with agolsidase beta in most patients. Intent-to-treat analysis of a double-blind, randomized, placebo-controlled, phase IV study, showed that, adjusted for on imbalance in baseline proteinuria, agalsidase beta significantly reduces by 53% the risk of a first clinical event (renal, cardiac and cerebrovascular), compared with placebo. Clinical benefits of ERT depend on patients' clinical status at baseline, therefore prompting for onset of ERT before irreversible damage occur and underlying the need to stratify patients' populations to better understand the outcome of ERT.
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PMID:[Development of an orphan drug to treat a genetic disease: the paradigm of agalsidase beta]. 1754 72

Fabry disease is a progressive and life-threatening glycolipid storage disorder affecting both males and females. The primary driver of the disease is the accumulation of glycolipids (globotriaosylceramide [GL-3]) in a variety of cell types, including vascular endothelial cells, a range of renal cell types, cardiomyocytes and neurons, which is caused by deficient activity of the lysosomal enzyme, alpha-galactosidase. The disease typically presents during childhood or adolescence. First manifestations reflect involvement of small nerve fibres of the peripheral and autonomic nervous systems. With age, severe complications involving the kidneys, heart and brain cause considerable morbidity and premature death. Outside the US, enzyme replacement therapy (ERT) with agalsidase alfa 0.2 mg/kg every other week (EOW) and agalsidase beta 1.0 mg/kg EOW is available for the treatment of patients with Fabry disease, while agalsidase beta 1.0 mg/kg EOW is the only approved drug in the US. To analyse the evidence for ERT, a systematic review of the literature was performed to identify prospectively designed randomized, controlled trials (RCTs) and open-label studies on the efficacy of agalsidase alfa and agalsidase beta. MEDLINE and EMBASE databases were searched; inclusion criteria for the systematic review were prospectively designed clinical studies evaluating ERT with quantifiable endpoints: double-blind and open-label studies were eligible. Exclusion criteria were review articles, case reports, case studies, letters to the editor and articles based on registry data (Fabry Outcome Survey or Fabry Registry). In addition, any studies with a retrospective design or data based on post hoc analyses were excluded. The evidence was reviewed with respect to the clinical benefits of ERT at the level of the end organ. A total of 9 RCTs and 23 open-label studies were identified for inclusion. The efficacy of ERT in Fabry disease has been measured against a variety of endpoints, the majority of which were subclinical parameters rather than clinical outcomes. Plasma levels of GL-3 together with accumulation in the kidney, heart and skin were the most commonly studied endpoints, followed by renal endpoints of proteinuria and glomerular filtration rate, whereas cardiac and neurological endpoints were not commonly studied. To date, only one RCT with ERT defined hard clinical outcomes in the form of cardiac, renal or cerebrovascular events, or death as its primary endpoint. The currently available data from prospective RCTs and open-label studies in patients with Fabry disease are more robust for ERT at a dose of 1 mg/kg EOW than a dose of 0.2 mg/kg EOW, although the beneficial effects of ERT with either dose or preparation are variable.
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PMID:Enzyme replacement therapy for Fabry disease: a systematic review of available evidence. 1985 24

The glomerular basement membrane (GBM) is a kind of net that remains in a state of dynamic equilibrium. Heparan sulfate proteoglycans (HSPGs) are among its most important components. There are much data indicating the significance of these proteoglycans in protecting proteins such as albumins from penetrating to the urine, although some new data indicate that loss of proteoglycans does not always lead to proteinuria. Heparanase is an enzyme which cleaves beta 1,4 D: -glucuronic bonds in sugar groups of HSPGs. Thus it is supposed that heparanase may have an important role in the pathogenesis of proteinuria. Increased heparanase expression and activity in the course of many glomerular diseases was observed. The most widely documented is the significance of heparanase in the pathogenesis of diabetic nephropathy. Moreover, heparanase acts as a signaling molecule and may influence the concentrations of active growth factors in the GBM. It is being investigated whether heparanase inhibition may cause decreased proteinuria. The heparanase inhibitor PI-88 (phosphomannopentaose sulfate) was effective as an antiproteinuric drug in an experimental model of membranous nephropathy. Nevertheless, this drug is burdened by some toxicity, so further investigations should be considered.
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PMID:The role of heparanase in diseases of the glomeruli. 2004 46

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