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)

Kawasaki disease (KD) is a systemic vasculitis with cardiac and noncardiac complications. Anti--endothelial cell antibodies (AECA) are found among many patients with KD. The aim of this study was to investigate the pathogenic role of AECA in KD using in vitro and in vivo experimental models. F(ab)2 fragments of IgG-AECA and IgM-AECA were affinity purified from a patient with active KD. Their endothelial binding and ability to induce a pro-adhesive and a pro-inflammatory phenotype were evaluated in vitro. Twenty Balb/C mice were immunized with KD-AECA or with control Ig (N-Ig) to induce AECA in a murine model by the idiotypic manipulation method. Both KD-AECA isotypes bind significantly to human umbilical vein endothelial cell (HUVEC) compared to N-Ig. The in vitro activity was demonstrated by the antibodies ability to activate endothelial cells resulting in increased IL-6 secretion, adhesion molecule expression and monocytic cell line (U937) adherence to HUVEC. Five of the mice that received KD-AECA developed murine AECA after 3 months. None of the mice that received N-Ig produced AECA. The murine AECA increased monocyte adhesion to EC in vitro, similarly to the AECA used for immunization. Furthermore, all the mice that developed AECA had proteinuria and IgG deposition in the renal mesangium. No histological or immunofluorescence evidence of cardiac vasculitis could be detected. AECA might play a role in the emergence of some of KD manifestations.
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PMID:The role of anti-endothelial cell antibodies in Kawasaki disease - in vitro and in vivo studies. 1239 Mar 10

Thromboembolic complications are often seen in patients with nephrotic syndrome. Markers of endothelial cell injury [thrombomodulin, intracellular adhesion molecule, vascular cell adhesion molecule, thrombin activatable fibrinolysis inhibitor (TAFI), protein Z, vascular endothelial growth factor, markers of thrombin and plasmin generation] were studied in 22 patients with nephrotic syndrome. All these parameters studied, except protein Z and D-dimers, were significantly higher in patients with nephrotic syndrome, whereas protein Z was significantly lower when compared with the healthy volunteers. None of the endothelial cell markers (thrombomodulin, P-selectin, E-selectin, intracellular adhesion molecule, vascular cell adhesion molecule), thrombin and plasmin generation markers (thrombin-antithrombin complexes, prothrombin fragments 1 + 2, plasmin-antiplasmin complexes, D-dimers), protein C, protein Z, vascular endothelial growth factor, and TAFI concentration and activity were directly correlated with the level of proteinuria, albumin, cholesterol, triglycerides or creatinine, except significant positive correlations between TAFI activity and serum creatinine, E-selectin and albumin as well as negative correlations between plasmin-antiplasmin complexes and proteinuria. In these patients, there is evidence of endothelial cell injury and probably secondary activation of the coagulation cascade. Elevated circulating TAFI antigen and activity might be a new link in the pathogenesis of impaired fibrinolysis and the progression of atherosclerosis in nephrotic syndrome. Protein Z deficiency might also contribute to the enhanced risk of thromboembolic complications in nephrotic syndrome.
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PMID:Markers of endothelial cell injury and thrombin activatable fibrinolysis inhibitor in nephrotic syndrome. 1243 47

Macrophages have been implicated in causing renal injury in both human and experimental kidney disease. The aim of the current study was to determine whether modulating the state of macrophage activation directly affects the capacity of these cells to cause renal injury. This was investigated using an adoptive transfer model in which macrophage activation can be manipulated in vitro, using interferon-gamma (IFN-gamma) or dexamethasone (Dex), and then macrophage-mediated renal injury determined in vivo. In this model, rats were made leukopenic by administration of cyclophosphamide (CyPh). Two days later (day 0), animals were injected with sheep anti-GBM serum followed by a single injection of rat NR8383 macrophages on day 1 and then killed 3 or 24 h after cell transfer. NR8383 macrophages were incubated IFN-gamma and/or Dex before adoptive transfer into animals. Induction of proteinuria and glomerular cell proliferation (PCNA+ cells) in this model was dependent on transfer of NR8383 macrophages. Exposure of macrophages to IFN-gamma for 18 h (but not 3 h) before transfer caused a twofold increase in the degree of proteinuria and glomerular cell proliferation compared with unstimulated cells (Nil versus IFN-gamma; P < 0.001). This was due to an increase in the number of transferred macrophages within the glomerulus and a significant increase in degree of renal injury per transferred glomerular macrophage. IFN-gamma increased iNOS and PDGF-B gene expression and upregulated adhesion molecule expression in NR8383 macrophages. In contrast, exposure of NR8383 cells to Dex for 18 h (but not 1 h) abrogated renal injury due to a failure of transferred macrophages to accumulate within the glomerulus. In addition, Dex abrogated renal injury caused by IFN-gamma-stimulated macrophages. In conclusion, activation of macrophages by IFN-gamma, independent of any effect on other leukocytes or renal cells, can substantially augment macrophage-mediated renal injury. This IFN-gamma augmentation of renal injury is sensitive to the action of glucocorticoids, which act directly on macrophages to prevent their recruitment to the inflamed glomerulus. This study provides the first evidence that it is possible to directly modulate macrophage-mediated renal injury.
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PMID:Interferon-gamma augments acute macrophage-mediated renal injury via a glucocorticoid-sensitive mechanism. 1266 Mar 23

Nephrin is a podocyte adhesion molecule located at the slit diaphragm between adjacent glomerular epithelial cells. Mutations in the gene encoding nephrin result in the absence of nephrin or alterations in nephrin causing massive proteinuria in patients with congenital nephrotic syndrome. Given the importance of nephrin to the structural integrity of the glomerular filtration barrier, we postulated that it might also be altered in acquired forms of nephrotic syndrome (NS). To test this hypothesis, frozen kidney biopsy sections from 29 pediatric patients with acquired NS and 5 controls were examined for expression of nephrin. The pathological diagnoses were minimal change disease (MCNS) (19) and focal segmental glomerulosclerosis (FSGS) (10). To determine if nephrin expression differed between children and adults with NS, 10 adult patients and 3 controls were also examined. Nephrin expression was evaluated by immunoperoxidase staining with a monoclonal antibody against the extracellular FnIII portion of human nephrin. In all cases, nephrin expression was seen along the glomerular basement membrane in a finely granular/linear pattern. Expression of nephrin was similar to controls in all 19 patients with MCNS and all 10 patients with FSGS. Areas of sclerosis in patients with FSGS did not demonstrate nephrin expression. A distinctly granular pattern to nephrin expression was seen in adult patients with NS as well as controls. These findings suggest that an alteration in nephrin expression is not a feature of acquired forms of NS in childhood.
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PMID:Expression of nephrin in acquired forms of nephrotic syndrome in childhood. 1474 39

GM-CSF has previously been demonstrated to be important in crescentic glomerulonephritis (GN). As both renal parenchymal cells and infiltrating inflammatory cells produce GM-CSF, their separate contributions to inflammatory renal injury were investigated by creation of two different types of GM-CSF chimeric mice: (1) GM-CSF-deficient (GM-CSF-/-)-->wild-type (WT) chimeras with leukocytes that are unable to produce GM-CSF and (2) WT-->GM-CSF-/- chimeras with deficient renal cell GM-CSF expression. Crescentic anti-glomerular basement membrane GN was induced in WT, GM-CSF(-/-)-->WT chimeras, WT-->GM-CSF-/- chimeras, and GM-CSF-/- mice by planting an antigen (sheep globulin) in their glomeruli. WT mice developed severe crescentic GN, whereas GM-CSF-/- were protected from development of disease. Glomerular T cell recruitment, CD40+ glomerular cells, and renal IFN-gamma and TNF expression were similar in both chimeras and WT mice but significantly reduced in GM-CSF-/- mice, indicating that either leukocyte or renal sources of GM-CSF are sufficient to drive these aspects of the inflammatory response. Restricted expression of GM-CSF revealed a major role for renal cell-derived GM-CSF but a minor role for leukocyte-derived GM-CSF in the formation of cellular crescents; glomerular MHC II expression; serum creatinine; and monocyte chemoattractant protein-1, vascular cellular adhesion molecule, and IL-1beta expression. Glomerular macrophage accumulation, proteinuria, and interstitial infiltrate were equivalent in both chimeric groups but intermediate between WT and GM-CSF-/-, indicating that both sources are required for the full development of glomerular injury in crescentic GN.
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PMID:Granulocyte macrophage colony-stimulating factor expression by both renal parenchymal and immune cells mediates murine crescentic glomerulonephritis. 1603 60

Mutations in CLCN5, which encodes the voltage-dependent Cl(-)/H(+)antiporter, CLC-5, cause Dent's disease. This disorder is characterized by low molecular-weight proteinuria, hypercalciuria, nephrocalcinosis and nephrolithiasis. Using a collecting duct cell model (mIMCD-3) in which endogenous clc-5 is disrupted by antisense clc-5 or overexpression of truncated clc-5, we demonstrate altered expression of the crystal adhesion molecule, annexin A2. Endogenously expressed annexin A2 is intracellular with limited plasma membrane localization. Following clc-5 disruption, there is both a marked increase in plasma membrane annexin A2 and an increase in cell surface crystal retention and agglomeration, which may be attenuated using pretreatment with anti-annexin A2 antibodies or wheat germ agglutinin lectin but not by concanavalin A. We hypothesize that in Dent's disease, endocytic failure leads to an accumulation at the plasma membrane of crystal-binding molecules that include annexin A2 leading to retention of calcium crystals and ultimately nephrocalcinosis and nephrolithiasis.
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PMID:Disruption of clc-5 leads to a redistribution of annexin A2 and promotes calcium crystal agglomeration in collecting duct epithelial cells. 1642 22

Sustained proteinuria and tubulointerstitial damage have been closely linked with progressive renal failure. Upon excess protein endocytosis, tubular epithelial cells are thought to produce mediators that promote inflammation, tubular degeneration, and fibrosis. This concept was tested in a transgenic mouse model with megalin deficiency. Application of an anti-glomerular basement membrane serum to transgenic megalin-deficient mice [Cre(+)/GN] and megalin-positive littermates [Cre(-)/GN] produced the typical glomerulonephritis (GN) with heavy proteinuria in both groups. Tubulointerstitial damages correlated closely with glomerular damages in pooled Cre(+)/GN and Cre(-)/GN mice. Owing to a mosaic pattern of megalin expression in the mutant mice, Cre(+)/GN kidneys permitted side-by-side analysis of megalin-deficient and megalin-positive tubules in the same kidney. Protein endocytosis was found only in megalin-positive cells. TGF-beta, intercellular adhesion molecule, vascular cellular adhesion molecule, endothelin-1, and cell proliferation were high in megalin-positive cells, whereas apoptosis, heat-shock protein 25, and osteopontin were enhanced in megalin-deficient cells. No fibrotic changes were associated with either phenotype. Tubular degeneration with interstitial inflammation was found only in nephrons with extensive crescentic lesions at the glomerulotubular junction. In sum, enhanced protein endocytosis indeed led to an upregulation of profibrotic mediators in a megalin-dependent way; however, there was no evidence that endocytosis played a pathogenetic role in the development of the tubulointerstitial disease.
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PMID:Abrogation of protein uptake through megalin-deficient proximal tubules does not safeguard against tubulointerstitial injury. 1751 21

Autoimmune crescentic glomerulonephritis is characterized by severe immune response with glomerular crescentic formation and fibrosis in the kidney. Recent studies indicate that overexpression of renal Smad7 attenuates both renal fibrosis and inflammation in rat remnant kidney. However, little attention has been paid to the potential role of TGF-beta/Smad signaling in autoimmune kidney disease. This study tested the hypothesis that blocking TGF-beta signaling by overexpression of Smad7 may have a therapeutic effect in a mouse model of autoimmune crescentic glomerulonephritis that was induced in C57BL/6 x DBA/2J F1 hybrid mice by giving DBA/2J donor lymphocytes. Smad7 gene was transfected into the kidney using the ultrasound-microbubble-mediated system. Results showed that overexpression of Smad7 blocked both renal fibrosis and inflammatory pathways in terms of Smad2/3 and NF-kappaB activation (P < 0.01), thereby inhibiting alpha-smooth muscle actin; collagen I, III, and IV accumulation; and expression of inflammatory cytokines (IL-1beta and IL-6), adhesion molecule/chemokine (intercellular adhesion molecule-1, monocyte chemoattractant protein-1), and inducible nitric oxide synthase (all P < 0.01). Leukocyte infiltration (CD4(+) cells and macrophages) was also suppressed (P < 0.005). Severe histologic damage (glomerular crescent formation and tubulointerstitial injury) and functional injury including proteinuria were significantly improved (all P < 0.05). This study provides important evidence that overexpression of Smad7 may have therapeutic potential for autoimmune kidney disease.
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PMID:Smad7 gene therapy ameliorates an autoimmune crescentic glomerulonephritis in mice. 1747 16

Chemokines and adhesion molecules are involved in early events of atherogenesis. In the present study, we investigated the effects of the uremic milieu on the expression of monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), soluble vascular adhesion molecule-1 (sVCAM-1) and soluble intercellular adhesion molecule-1 (sICAM-1) and their relationship to cardiovascular status. Plasma samples were obtained from patients in different stages of chronic kidney disease (CKD). Cardiovascular status was evaluated by intima-media thickness and endothelial dysfunction by flow mediation dilatation and proteinuria. In vitro studies were performed using human umbilical endothelial cells exposed to uremic plasma or plasma from healthy subjects. MCP-1, IL-8, sVCAM-1 and sICAM-1 levels in plasma and in supernatant were analyzed by enzyme-linked immunosorbent assay. The population consisted of 73 (mean age 57 years; 48% males) CKD patients with glomerular filtration rate (GFR) of 37 +/- 2 ml/min. MCP-1 and sVCAM-1 plasma levels were negatively correlated with GFR (rho = -0.40, p < 0.0005 and rho = -0.42, p < 0.0005, respectively). Fibrinogen was positively correlated with MCP-1, sICAM-1 and sVCAM-1 (rho = 0.33, p < 0.005, rho = 0.32, p < 0.05 and rho = 0.25, p < 0.05, respectively) and ultra-high-sensitivity C-reactive protein was positively correlated with sICAM-1 (rho = 0.25, p < 0.0005). Plasma IL-8 had a significant positive correlation with proteinuria (rho = 0.31, p < 0.01). There was a time- and CKD-stage-dependent MCP-1, IL-8 and sVCAM-1 endothelial expression (p < 0.05). In summary, plasma levels of markers of endothelial cell activation (MCP-1 and sVCAM-1) are increased in more advanced CKD. Exposure of endothelial cells to uremic plasma results in a time- and CKD-stage-dependent increased expression of MCP-1, IL-8 and sVCAM-1, suggesting a link between vascular activation, systemic inflammation and uremic toxicity. Future studies are necessary to investigate whether these biomarkers add predictive value in comparison to the previously described ones. Also, endothelial response to uremic toxicity should be viewed as a potential target for intervention in order to reduce morbidity and mortality in CKD-related cardiovascular disease.
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PMID:Increased plasma and endothelial cell expression of chemokines and adhesion molecules in chronic kidney disease. 1914 93

The reaction of mesangial cells with aberrantly glycosylated IgA1 has been implicated in the etiology of IgA nephropathy (IgAN). Tumor necrosis factor, which is assumed to mediate the interaction between mesangial cells and podocytes, also induces the expression of platelet-activating factor (PAF). In this study, we determined whether PAF affects the expression of nephrin (an adhesion molecule critical to glomerular permselectivity) and cytoskeletal F-actin organization in podocytes. We treated human mesangial cells with atypically glycosylated IgA1 either prepared in vitro or derived from the sera of patients with IgAN. We then prepared conditioned media from these cells and added them to cultured human podocytes in the presence of PAF receptor antagonists. Podocytes transfected to overexpress acetylhydrolase, the main catabolic enzyme of PAF, served as controls. Downregulation of nephrin expression and F-actin reorganization occurred when podocytes were cultured with mesangial cell-conditioned medium. Preincubation of podocytes with a PAF receptor antagonist prevented the loss and redistribution of nephrin. In control podocytes overexpressing acetylhydrolase, nephrin loss was abrogated. Our results suggest that atypically glycosylated IgA-induced PAF from mesangial cells is a mediator of podocyte changes, which, when more directly tested elsewhere, were found to be associated with proteinuria. Hence, it is possible that these in vitro findings may be relevant to the proteinuria of IgAN.
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PMID:Aberrantly glycosylated IgA1 induces mesangial cells to produce platelet-activating factor that mediates nephrin loss in cultured podocytes. 2001 69


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