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)

Maleate treatment of rats induces transport defects similar to those seen in the Fanconi syndrome (glycosuria, aminoaciduria, phosphaturia, proteinuria, etc.) and causes an accumulation of apical vesicles in proximal tubule epithelial cells. Because the apical membrane glycoprotein, gp330, is a receptor associated with the apical endocytotic and recycling apparatus in these cells, we examined the effect of maleate on the distribution of this protein and other brush border markers. Rats received sodium maleate (400 mg/kg ip) and were killed at various times between 45 min and 3 h; kidneys were perfusion fixed with paraformaldehyde-lysine-periodate before processing for immunofluorescence and immunoelectron microscopy. In control rats, staining with a polyclonal or monoclonal gp330 antibody showed a uniform distribution on the brush border and in coated pits of all proximal tubule cells. In the S3 segments, the immunofluorescence labeling of the microvilli was generally uniform but at times showed spike labeling, suggesting that gp330 sheds easily from the apical membrane. After maleate treatment, the staining intensity of the brush border was decreased in all proximal tubule segments, and cytoplasmic streaks as well as an intense vacuolar staining were seen. In the S3 segment, a remarkable mosaic pattern of staining was observed, with the brush border of some cells being completely negative, while adjacent cells showed an apparently normal staining pattern. These results were confirmed at the electron microscope level, using the protein A-gold technique. Maleate had no effect on the distribution or staining intensity of four other brush border markers, dipeptidyl peptidase IV, and various lectins (Helix pomatia lectin, peanut lectin, elderberry bark lectin). The urinary excretion of gp330 occurs in normal rats and was already increased as early as 1 h after maleate injection and remained at a twofold increment between 6 and 24 h. These data suggest that the generalized membrane transport derangement seen in this experimental Fanconi syndrome could occur via a specific effect on gp330, which seems to block endocytosis and the recycling apparatus at the late endosome level and inhibits the formation of new dense apical tubules.
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PMID:Specific effect of maleate on an apical membrane glycoprotein (gp330) in proximal tubule of rat kidneys. 889 22

In diabetic nephropathy a major current concept for pathogenesis is increased collagen accumulation in the glomerulus by increased collagen synthesis and decreased degradation. In the present study, we tested the hypothesis whether arginine is able to influence kidney lipid peroxidation, glycoxidation, collagen accumulation, glucose-mediated cross-linking, hydroxy radical attack, protein oxidation, nitric oxide formation and albuminuria in the diabetic kk mouse. Ten diabetic kk mice were given arginine 50 mg/kg body weight, 10 diabetic kk mice were not treated and used as negative controls and 10 kk mice were kept as healthy controls. Our results show that oral administration of low-dose arginine reduces kidney collagen accumulation as reflected by kidney hydroxyproline, cross-linking as reflected by pentosidine, lipid peroxidation, glycoxidation as reflected by carboxymethyl lysine, kidney weight and albuminuria in the diabetic kk mouse. Albuminuria in untreated animals was closely correlated with lipid peroxidation. Our results in the spontaneously diabetic kk mouse representing type 2 diabetes mellitus therefore confirm and extend recent findings of collagen reduction by arginine in a different animal model. The mechanism of reducing proteinuria can be assigned to the blocking of lipid peroxidation products by L-arginine.
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PMID:Arginine reduces kidney collagen accumulation, cross-linking, lipid peroxidation, glycoxidation, kidney weight and albuminuria in the diabetic kk mouse. 904 44

Ciclosporin A (CsA) can reduce proteinuria in various forms of human and experimental glomerulopathies. This antiproteinuric effect can be the result of a decrease of immunological damage, a decrease in the glomerular filtration rate (GFR), or a change in the permselective properties of the glomerular capillary wall. In this study we investigated the effect of CsA on Adriamycin-induced nephropathy in rats. A single intravenous injection of Adriamycin (5 mg/kg body weight) induced a severe nephrotic syndrome with a massive albuminuria (+/- 400 mg/24 h from 3 weeks onwards) and a hypoalbuminemia (+/- 7 mg/ml after 5 weeks). The IgG/albumin selectivity index was 0.16 +/- 0.05, indicating a preferential loss of albumin. A 5-day treatment with CsA reduced the albumin excretion by almost 50% (from 336 +/- 91 to 178 +/- 58 mg/24 h; p = 0.002) and induced an increase in the serum albumin level (from 7.1 +/- 4.1 to 12.8 +/- 3.2 mg/ml; p = 0.002) in contrast to the vehicle olive oil (OO). CsA also decreased the GFR by 40% (from 0.74 +/- 0.11 to 0.41 +/- 0.11 mg/ml/100 g body weight; p = 0.002). Albuminuria corrected for the GFR (fractional excretion of albumin, FE(alb)) was still significantly lower in CsA-treated than in OO-treated animals (FE(alb) CsA: 1.35 +/- 0.88, FE(alb) OO: 3.17 +/- 2.29%; p = 0.0005). This suggests that other factors are also involved in the reduction of albuminuria. To exclude that CsA has an effect on the tubular reabsorption of albumin, we evaluated the blockade of the tubular reabsorption by lysine and found no difference in albuminuria between the CsA- and OO-treated groups. These experiments suggest that the antiproteinuric effect of CsA is not (only) due to a decrease in the GFR, but also to a decrease of the enhanced permeability of the glomerular capillary wall for albumin.
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PMID:Antiproteinuric effect of ciclosporin A in adriamycin nephropathy in rats. 906 57

Cytokines play a pivotal role in synthesis and deposition of extracellular matrix in chronic renal failure (CRF). The proinflammatory properties of monocyte chemoattractant protein (MCP)-1 make it an ideal candidate cytokine for the production of interstitial inflammation in CRF. To investigate the possible role of proteinuria in inducing proximal tubular (PT) MCP-1, MCP-1 mRNA levels were measured by Northern blot and reverse transcription PCR in confluent monolayers of PT cells in primary culture in media containing a variety of proteins. PT cells produced MCP-1 mRNA in response to bovine serum albumin (BSA), delipidated BSA (dBSA; 0.5 to 30 mg/ml), holotransferrin, and apotransferrin (1 to 8 mg/ml). Unstimulated PT cells expressed very low levels of MCP-1 mRNA, detectable by reverse transcription PCR but not by Northern blot. The expression of MCP-1 mRNA reached a peak (sixfold greater than control) within 4 h of exposure to dBSA and was maintained for at least 24 h with continued exposure. Removal of dBSA from the media led to a rapid decline in MCP-1 mRNA expression. dBSA-induced MCP-1 expression was inhibited by lysine, an inhibitor of protein uptake, and reproduced by dBSA purified by gel and size-selective filtration. dBSA influenced MCP-1 expression at the level of transcription and probably translation, as evidenced by abrogation of MCP-1 by actinomycin D and superinduction with the protein synthesis inhibitor cycloheximide. The concentration of MCP-1 protein in response to dBSA added to the apical surface of PT cells was 2.4-fold greater in basolateral than in apical media, indicating basolateral secretion of MCP-1 protein. In summary, PT cell MCP-1 mRNA and protein expression are upregulated by albumin and transferrin, in concentrations similar to those of proteinuric urine. This effect could explain the link between proteinuria and interstitial inflammation in CRF.
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PMID:Induction of monocyte chemoattractant protein-1 in proximal tubule cells by urinary protein. 933 81

Proteinuria has been invoked as a cause of tubulointerstitial injury in chronic renal disease, and in vivo studies have suggested indirectly the particular nephrotoxicity of one urinary protein holotransferrin (Tf-Fe). However, to date there has been no direct evidence for the nephrotoxicity of Tf-Fe. To examine the potential cytotoxicity of Tf-Fe and the mechanism involved, and to compare this to another urinary protein albumin, rat proximal tubule cells were studied in primary culture. Tf-Fe at pH 6.0 caused functional and ultrastructural injury, but no cytotoxicity was seen with cells exposed to albumin, apotransferrin (transferrin), or Tf-Fe at pH 7.4. The influence of pH on Tf-Fe-induced cytotoxicity was not due to pH per se, but could be explained by an effect on Tf-Fe uptake. At pH 6.0, uptake of 125I-Tf-Fe (3.55 +/- 0.05 versus 1.25 +/- 0.10 fmol/dish, P < 0.01) and intracellular iron concentration (1.14 +/- 0.25 versus 0.46 +/- 0.23 nmol/dish, P < 0.01) were increased compared with values at pH 7.4. In contrast, pH 6.0 did not increase iron uptake from FeCl3. Lysine (100 mM) inhibited Tf-Fe uptake, decreased intracellular iron concentration, and attenuated Tf-Fe-induced cytotoxicity. The iron chelator des-ferrioxamine (200 microM) and hydroxyl radical scavenger dimethylpyrroline N-oxide (32 mM) abolished lactate dehydrogenase leakage induced by Tf-Fe at pH 6.0. Lipid peroxidation, as assessed by production of malondialdehyde, preceded lactate dehydrogenase leakage. In summary, holotransferrin, but not albumin, is toxic to rat proximal tubule cells, a pH-dependent effect involving its uptake into tubule cells, its iron moiety, and its lipid peroxidation.
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PMID:Toxicity of holotransferrin but not albumin in proximal tubule cells in primary culture. 944 90

In a rat model of glomerular immune injury induced by administration of anti-glomerular basement membrane antibody and resembling human rapidly progressive glomerulonephritis, we explored whether activation of inducible nitric oxide synthase (iNOS) regulates synthesis of eicosanoids originating from cyclooxygenation or lipoxygenation of arachidonic acid. At early stages (24 hr) of injury, inhibition of iNOS using the selective inhibitor L-N6-(1-iminoethyl) lysine (L-NIL) at doses sufficient to reduce urinary excretion of nitrate/nitrite, reduced glomerular synthesis of the prostaglandins PGE2 and PGI2, but had no effect on that of thromboxane A2 (TxA2). The syntheses of 5-hydroxyeicosatetraenoic acid (HETE), 15-HETE and leukotriene B4 (LTB4) were also reduced. That of 12-HETE remained unchanged. We also explored the effect of arachidonate cyclooxygenation and lipoxygenation eicosanoids on iNOS expression. Administration of the cyclooxygenase (COX) inhibitor, indomethacin, at doses sufficient to inhibit glomerular prostaglandin synthesis, increased iNOS mRNA levels in glomeruli. Administration of the 5-lipoxygenase (5-LO) inhibitor, MK-0591, at doses sufficient to inhibit glomerular LTB4 synthesis also increased iNOS mRNA. The effect of 5-LO inhibition on iNOS expression was more pronounced than that of COX inhibition. In nephritic animals given the iNOS inhibitor, L-NIL, or indomethacin proteinuria worsened. In those given the 5-lipoxygenase inhibitor there was no change in urine protein excretion. These observations point to regulatory interactions between the arachidonic acid and the L-arginine: NO pathways in glomerulonephritis. These interactions are of importance in considering antiinflammatory strategies based on inhibition of iNOS or of specific eicosanoids.
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PMID:Regulatory interactions between inducible nitric oxide synthase and eicosanoids in glomerular immune injury. 950 10

Mutations in the Wilms' tumor suppressor gene (WT1) are linked with Denys-Drash syndrome (DDS), a rare childhood disease characterized by diffuse mesangial sclerosis and renal failure of early onset, XY pseudohermaphroditism, and high risk of Wilms' tumor. KTS (lysine-threonine-serine) splice site mutations in WT1 intron 9 have been described in patients with Frasier syndrome, another rare syndrome defined by focal and segmental glomerulosclerosis (FSGS), XY pseudohermaphroditism, and frequent occurrence of gonadoblastoma. Cases of Frasier syndrome raise the question whether splice site mutations may also be found in XX females with isolated FSGS. A girl (index case) presented with the nephrotic syndrome at 9 mo of age. The diagnosis of DDS was based on the finding of diffuse mesangial sclerosis in the kidney biopsy and of a XY karyotype. The index case's mother had had proteinuria since she was 6 years of age. A renal biopsy was performed when she was 28 and disclosed FSGS. The same splice site mutation in intron 9 (WT1 1228+5 G-->A) involving one allele was found in the child and in her mother, but not in other members of the kindred (including the parents, the two brothers, and the two sisters of the index case's mother) who were free of renal symptoms. Quantification of WT1 +KTS/-KTS isoforms in the index case's father and one index case's maternal uncle showed a normal +KTS/-KTS ratio of 1.50. In contrast, the index case and her mother had a low ratio (0.40 and 0.34, respectively), within the range reported in Frasier syndrome. In conclusion, this study shows that the KTS splice site mutation is not specific for Frasier syndrome, but that it can also be found in DDS and in a normal female (XX) with FSGS, a woman who achieved normal pregnancy. It is suggested that WT1 splice site mutations should be sought in phenotypically normal females who present with FSGS or with related glomerulopathies of early onset.
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PMID:Mother-to-child transmitted WT1 splice-site mutation is responsible for distinct glomerular diseases. 1050

Increased NO synthesis, due to inducible NO synthase (iNOS) activity, is found in macrophage-associated glomerulonephritis. Little is known about NO in neutrophil-dependent immune complex inflammation, and its role remains controversial. We therefore studied early phase heterologous nephrotoxic nephritis (HNTN) induced in rats by nephrotoxic globulin and the effects of selective iNOS inhibition of this model. At 2 h of the model iNOS mRNA was induced and nitrite (NO-2) was generated in glomeruli incubated ex vivo (5.2 +/- 1.0 nmol/2000 glomeruli per 24 h). There were 14.7 +/- 2.2 polymorphonuclear neutrophils (PMN)/glomerulus (normal controls 0.1 +/- 0.1). At 8 h urinary protein was 69 +/- 15.3 (normal controls 0. 6 +/- 0.2 mg/24 h). Peritoneal PMN expressed iNOS and produced significant NO-2 (basal 11.2 +/- 0.3 nmol/106 cells per 24 h). Selective iNOS inhibition with L-N6-(1-iminoethyl)-lysine (L-NIL) in vitro inhibited nephritic glomerular and PMN NO-2 synthesis. In HNTN L-NIL in vivo significantly suppressed elevated plasma NO-2/NO-3 levels (representative experiment: 17 +/- 2 microM, untreated 40 +/- 4 microM, P = < 0.01, normal control 18 +/- 2 microM). This inhibition did not affect leucocyte infiltration into glomeruli or induce thrombosis. There was no consistent effect on proteinuria. This is the first demonstration of glomerular iNOS induction and high output NO production in the acute phase of PMN-dependent acute immune complex glomerulonephritis. Selective iNOS inhibition does not affect the primary mechanism of injury (leucocyte infiltration) in this model.
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PMID:Induced nitric oxide (NO) synthesis in heterologous nephrotoxic nephritis; effects of selective inhibition in neutrophil-dependent glomerulonephritis. 1054 Jan 96

Analysis of glomerular anionic charge in human renal biopsy specimens has been restricted previously to staining of sites at the electron microscopic level, which is a product that needs skills and precludes a wide observable area. The introduction of a new tool, confocal laser scanning microscopy together with FITC conjugated poly-L-lysine as a cationic tracer, which demonstrates fixed anionic sites in thin sections from routinely formalin-fixed and paraffin-embedded renal biopsy tissue, has now enabled glomerular charge at light microscopic level. In this method, the patterns of staining in tissue showing minimal change nephrotic syndrome (MCNS) indicate that the intensity of anionic charge in 4 children with heavy proteinuria was significantly less than that in 7 children without proteinuria at remission, supporting previous observations using electron microscopy. Furthermore, staining the serial sections after methylation or saponification revealed that carboxyl components such as sialic acid may be responsible for proteinuria. We anticipate that this method may facilitate the investigation of the participation of charged components in the pathogenesis of MCNS and their role in relation to glomerular proteinuria.
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PMID:[Analysis of glomerular anionic charge status in renal biopsy specimens of childhood minimal change nephrotic syndrome using confocal laser scanning microscopy]. 1073 9

Nitric oxide (NO) regulates inflammatory responses partly by cell-specific inhibition of the transcription factor nuclear factor kappaB (NF-kappaB). This study investigated the effect of continuous oral administration of an NO donor (molsidomine [Mol]), NO precursor (L-arginine [L-arg]), or selective inhibitors of inducible NO synthase (iNOS; aminoguanidine [AG], L-N(6)-(1-iminoethyl)lysine [L-NIL]) on the progression of tubulointerstitial inflammation and NF-kappaB activation in a non-immune model of chronic glomerular disease (Adriamycin nephropathy [AN]), from day 8 until day 30 after disease induction. On day 30, rats with AN had heavy proteinuria, reduced creatinine clearance, and tubulointerstitial disease. Treatment with both AG and L-NIL exacerbated the progression of AN as evidenced by (1) increased renal cortical malondialdehyde; (2) reduced creatinine clearance; and (3) increased tubular atrophy, interstitial volume, and monocyte infiltration. Unexpectedly, Mol also increased renal malondialdehyde and worsened tubular injury, whereas L-arg had no effect. The increase in renal cortical NF-kappaB activation in AN was not altered by AG, L-NIL, or Mol, but the mRNA expression of monocyte chemoattractant protein-1, interleukin-10, and osteopontin were elevated in these groups. Nitrite release from kidney slices reduced in AN. Treatment with Mol restored renal nitrite release to normal, whereas neither L-arg nor the NOS inhibitors had an effect. It is concluded that endogenous iNOS-derived NO has a protective role against tubulointerstitial injury and cytokine production in AN. However, the pro-oxidant activity of NO donors may limit their potential benefit in proteinuric renal disease.
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PMID:Pharmacologic modulators of nitric oxide exacerbate tubulointerstitial inflammation in proteinuric rats. 1146 42


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