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)

Chronic progressive membranous nephropathy (MN) in humans is characterized by thickening of the glomerular basement membrane (GBM) with formation of spikes which contain laminin and other extracellular matrix (ECM) proteins. We have utilized two models of MN in the rat (active and passive Heymann nephritis, AICN, PHN) to define the sequential changes in composition of GBM as they relate to changes in glomerular gene expression for ECM components, altered permeability and morphological changes. Renal biopsies obtained during the course of AICN and PHN were immunostained for various ECM proteins and total glomerular RNA was hybridized with cDNA probes specific for laminin B2-chain, s-laminin, and types I and IV collagen. In addition, the ability of anti-glomerular epithelial cell (GEC) antibody and complement on rat GEC in culture to induce laminin release or laminin and s-laminin mRNA expression was determined. The results demonstrate that at weeks 12, 16, and 20 of AICN, immunostaining for laminin, s-laminin, fibronectin, entactin, and heparan sulfate proteoglycan increased in the GBM in a spike-like pattern. Concomitantly, glomerular mRNA levels of laminin B2-chain and of s-laminin increased. Type IV collagen protein and gene expression remained unchanged or decreased. No glomerular immunostaining for type I collagen occurred during AICN despite increased expression of mRNA for this collagen type. In contrast to AICN, in PHN no pronounced changes of the glomerular ECM occurred, except for transient expression of type I collagen mRNA in whole glomerular RNA and type I collagen protein the GEC cytoplasm. Stimulation of GEC in culture with anti-GEC antibody and complement also failed to induce transcription of laminin or s-laminin mRNA or the release of laminin protein. These findings suggest that the polyantigenic expansion of GBM which occurs in chronic experimental MN may be stimulated by factors different from the C5b-9 mediated processes that cause the initial proteinuria.
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PMID:Altered glomerular extracellular matrix synthesis in experimental membranous nephropathy. 138 96

Patients infected with human immunodeficiency virus type 1 (HIV-1) develop a renal syndrome characterized by proteinuria, renal failure, and focal segmental glomerulosclerosis. By using a noninfectious HIV-1 DNA construct lacking the gag and pol genes, three transgenic mouse lines have been generated that develop a syndrome remarkably similar to the human disease. In the present study, we have characterized in detail one of these lines, Tg26. In Tg26 mice, proteinuria was detectable at approximately 24 days of age, followed by severe nephrotic syndrome and rapid progression to end-stage renal failure. Renal histology showed focal segmental glomerulosclerosis and microcystic tubular dilatation. Indirect immunofluorescence studies demonstrated increased accumulation of the basement membrane components laminin, collagen type IV, and heparan sulfate proteoglycan. The viral protein Rev was present in sclerotic glomeruli. Northern blot analysis of total renal RNA showed expression of viral genes prior to the appearance of histologic renal disease, with greatly diminished viral gene expression late in the disease course. Kidneys from transgenic mice expressed increased steady-state levels of collagen alpha 1(IV) mRNA when glomerulosclerosis was present. We conclude that the presence of HIV-1 genes is associated with progressive renal dysfunction and glomerulosclerosis in transgenic mice.
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PMID:Progressive glomerulosclerosis and enhanced renal accumulation of basement membrane components in mice transgenic for human immunodeficiency virus type 1 genes. 154 49

After immunization of mice with partially-purified heparan sulfate proteoglycan (HSPG) isolated from rat glomeruli, a monoclonal antibody (mAb JM-403) was obtained, which was directed against heparan sulfate (HS), the glycosaminoglycan side chain of HSPG. In ELISA it reacted with isolated human glomerular basement membrane (GBM) HSPG, HS and hyaluronic acid, but not with the core protein of human GBM HSPG, and not with chondroitin sulfate A and C, dermatan sulfate, keratan sulfate and heparin. Furthermore, it did not bind to laminin, collagen type IV or fibronectin. Specificity of JM-403 for HS was also suggested by results of inhibition studies, which found that intact HSPG and HS, but not the core protein, inhibited the binding of JM-403 to HS. In indirect immunofluorescence on cryostat sections of rat kidney, a fine granular to linear staining of the GBM was observed, along with a variable staining of the other renal basement membranes. Pretreatment of the sections with heparitinase completely prevented the binding of mAb JM-403, whereas pretreatment with chondroitinase ABC or hyaluronidase had no effect. The precise binding site of mAb JM-403 was investigated by indirect immunoelectron microscopy. It revealed a diffuse staining of the whole width of the GBM. One hour after intravenous injection of JM-403 into rats, the mAb was detected along the glomerular capillary wall in a fine granular pattern, which shifted towards a more mesangial localization after 24 hours. No binding was observed anymore by day 15. Intravenous injection induced a dose-dependent, transient and selective proteinuria that was maximal immediately after the injection.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A monoclonal antibody against GBM heparan sulfate induces an acute selective proteinuria in rats. 159 46

Renal glomerular basement membranes (GBMs) exhibit a charge-selective barrier, consisting of heparan sulfate proteoglycan (HSPG) that restricts the passage of anionic molecules into the urine. Previous efforts to localize the HSPG core protein within various layers of the GBM have been contradictory. Furthermore, attempts to correlate proteinuria in several disease states with a decrease in anionic sites of HSPG core protein have yielded conflicting results. When antibodies to HSPG from the EHS tumor matrix [anti-(EHS) HSPG] and GBMs [anti-(GBM) HSPG] were used together with immunogold to label renal tissues from puromycin aminonucleoside nephrotic (PAN) rats, immunolabeling results indicated that a portion of the protein core recognized by anti-(EHS) HSPG was significantly reduced, while immunolabeling with anti-(GBM) HSPG was only slightly reduced in early PAN. Anionic sites (stained with the cationic probe, polyethyleneimine) within the lamina rara externa of the GBM remained unaltered throughout the course of PAN.
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PMID:Anionic site and immunogold quantitation of heparan sulfate proteoglycans in glomerular basement membranes of puromycin aminonucleoside nephrotic rats. 175 Jul 10

The changes in glomerular extracellular matrices components in diabetic nephropathy were investigated. Indirect immunofluorescence staining, using polyclonal antibodies to heparan sulfate proteoglycan (HS-PG), laminin, type IV collagen, and fibronectin was carried out on renal specimens obtained by needle biopsy. Immunofluorescence intensity and distribution were observed. HS-PG and laminin decreased in the capillary walls; on the other hand, type IV collagen and fibronectin tended to increase in the mesangial area. HS-PG and laminin decreased in inverse proportion to sclerosis grades and proteinuria. These changes seemed to play an important role in progression of diabetic glomerulosclerosis.
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PMID:Changes in glomerular extracellular matrices components in diabetic nephropathy. 177 41

Angiotensin converting enzyme (ACE) inhibitors, particularly enalapril and captopril, have been shown to decrease proteinuria in diabetic animals and human subjects. Since heparan sulfate proteoglycan confers a negative charge on the glomerular basement membrane, and either decreased synthesis or loss of this charge causes albuminuria in diabetic animals, we examined the possibility that enalapril prevents albuminuria through glomerular preservation of heparan sulfate in long-term diabetic rats. A total of 22 male Wistar rats were used in the study. Diabetes was induced in 15 rats by a single intraperitoneal injection of streptozotocin (60 mg/kg). The remaining 7 rats received buffer. One week following induction of diabetes, 8 diabetic rats were allowed to drink tap water containing enalapril at a concentration of 50 mg/liter; the remaining 7 diabetic and 7 nondiabetic rats were given only tap water. The drug treatment was continued for 20 weeks. Systolic blood pressure and 24-hr urinary excretion of albumin were measured at 2, 8, 16, and 20 weeks. At the end of 20 weeks, all rats were killed, kidneys were removed, and glomeruli were isolated by differential sieving technique. Total glycosaminoglycan and heparan sulfate synthesis was determined by incubating glomeruli in the presence of [35S]sulfate. Characterization of heparan sulfate was performed by ion-exchange chromatography. Systolic blood pressures were significantly lower in enalapril-treated diabetic rats compared to untreated diabetic rats. Diabetic glomeruli synthesized less heparan sulfate than glomeruli from nondiabetic rats. Also, glomerular heparan sulfate content of diabetics was significantly lower than that of nondiabetics. Further characterization of heparan sulfate showed that the fraction eluted with 1 M NaCl was significantly lower and the fraction eluted with 1.25 M NaCl significantly higher in diabetic than in normal rats. Enalapril treatment normalized not only glomerular synthesis and content but also various fractions of heparan sulfate in diabetic rats. Diabetic rats excreted increased quantities of heparan sulfate and albumin than nondiabetic rats. Enalapril therapy prevented both these increases in diabetic rats. These data suggest that enalapril treatment improves albuminuria through preservation of glomerular heparan sulfate and prevention of its urinary loss in diabetic rats.
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PMID:Enalapril improves albuminuria by preventing glomerular loss of heparan sulfate in diabetic rats. 201 5

Correlations between the steady-state mRNA levels of extracellular matrices using specific cDNA probes for the alpha 1 chain of type IV collagen (alpha 1 (IV) chain); laminin A, B1, and B2 chains; and heparan sulfate proteoglycan (HSPG); and glomerular injuries in ddY mice were evaluated. Eight-, sixteen- and forty-week-old ddY mice were used in this study. ICR mice of the same age served as control. Extracted total RNA of pooled kidneys was fixed on a filter and then hybridized with the cDNA probes. Renal cryostat sections were incubated with rabbit anti-mouse type IV collagen, laminin, and HSPG antisera and then stained with FITC-labeled goat anti-rabbit IgG antiserum. The sections were also stained with FITC-labeled goat anti-mouse IgA, IgM, IgG, and C3 antisera. In light microscopy, the average number of glomerular cells was calculated at each age. Increased expression of extracellular matrices genes for the alpha 1(IV) chain; laminin A, B1, and B2 chains; and HSPG was found in renal tissues of ddY mice. Staining of type IV collagen, laminin, and HSPG was observed in renal tissues of ddY mice at each age. Increased proteinuria in 40-week-old ddY mice might be related to the decrease in glomerular basement membrane HSPG which acts as the anionic sites in such areas. Marked proliferation and or expansion of glomerular cells and mesangial matrices were observed in 40 week-old-ddY mice. The intensity of IgA and C3 deposits in the glomeruli was parallel to the levels of mRNA for such components.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Altered steady-state levels of mRNA coding for extracellular matrices in renal tissues of ddY mice, an animal model for IgA nephropathy. 202 56

The present studies were designed to analyze mRNA levels of basement membrane components including collagen IV, laminin, and heparan sulfate proteoglycan (HSPG) in the course of puromycin aminonucleoside (PAN) nephrosis. mRNA levels for alpha 1 (IV) chain; laminin A, B1, and B2 chains; and HSPG were measured in glomeruli of PAN nephrotic rats 0, 2, 8, 14, and 20 days after PAN injection. In the nephrotic stage of PAN nephrosis (on the 8th day), mRNA levels for alpha 1 (IV) chain and laminin A, B1, and B2 chains increased, whereas those for HSPG decreased. The anionic sites in glomerular basement membrane stained by polyethyleneimine were smaller in size and fewer in number in PAN nephrotic rats than they were in control rats. In the remission stage of PAN nephrosis (on the 20th day), however, mRNA levels for alpha 1 (IV) chain and laminin A, B1, and B2 chains decreased, whereas mRNA levels for HSPG increased. Polyethyleneimine aggregates in this stage appeared to be larger and more intense than those in the nephrotic stage. These results indicate that the expression of basement membrane genes for alpha 1 (IV), laminin, and HSPG was abnormally regulated in PAN nephrosis and that this abnormal gene regulation might contribute to the development of proteinuria.
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PMID:Modulation of basement membrane component gene expression in glomeruli of aminonucleoside nephrosis. 203 May 78

This study deals with the quantification of mRNA of basement membrane components (laminin, type IV collagen, heparan sulfate proteoglycan) and type I collagen in focal glomerular sclerosis induced by the aminonucleoside of puromycin (PAN) in rats. PAN (15 mg/100 g B.W.) was injected intraperitoneally to male Sprague-Dawley rats on day 0. On day 22, the right kidney was removed from group II and III. Rats in group III received injections of PAN (5 mg/100 g B.W.) on day 27, 34 and 41. Rats in group II received injections of 0.9% NaCl instead of PAN. Remnant kidneys were removed on days 48, 60 and 80 and processed for RNA isolation and histopathological study. Glomerular RNAs were isolated using guanidinium thiocyanate and then dotted onto nylon membrane. Filters were hybridized with specific cDNA probes and exposed to film for analysis by densitometer. FGS was detected in 70% of glomeruli on day 80 in group II. All the basement membrane components and type I collagen were accumulated in the sclerotic areas. The mRNA coding for laminin and type IV collagen continued to increase in group III till day 80. The mRNA for HSPG decreased when the urinary protein excretion was maximum on day 48, then increased with the remission of proteinuria. The type I collagen mRNA also increased during the course of the FGS. We suggest that decrease of mRNA for HSPG may play an important role in the development of proteinuria in PAN nephrosis and increase of mRNA coding for laminin, type IV collagen and type I collagen may be involved in focal glomerular sclerosis.
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PMID:[Changes in the expression of basement membrane and type I collagen gene in focal glomerular sclerosis (FGS)]. 208 58

Heparan sulfate proteoglycan (HSPG) has been identified as an important determinant of glomerular permselectivity. We have previously reported that glomerular epithelial cells in culture synthesize HSPG, suggesting that in vivo these cells contribute to the HSPG present in the glomerular basement membrane. In this study we examined the effects of dexamethasone on the metabolism of HSPG core protein in cultured glomerular epithelial cells. Dexamethasone caused a dose-dependent and time-dependent increase in the HSPG core protein content of the cells. This effect was not seen with an equimolar concentration of aldosterone, indicating it was selective for dexamethasone. Dexamethasone caused a significant inhibition in 3H-leucine incorporation into de novo synthesized proteins at concentrations that caused maximum increment in the HSPG core protein content. These findings support the interpretation that HSPG core protein is a selective target for dexamethasone. Actinomycin-D completely abrogated the dexamethasone effect on HSPG core protein content, implying that enhanced transcription may be the major mechanism underlying the dexamethasone-induced increment in HSPG core protein content. Our findings suggest that glucocorticoids have important effects on the metabolism of the core protein moiety of heparan sulfate proteoglycan. Furthermore, these data imply that the glucocorticoid-induced amelioration of proteinuria could involve metabolic effects on the local determinants of glomerular permselectivity (e.g., HSPG) in addition to their well-known systemic anti-inflammatory effects.
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PMID:Dexamethasone increases heparan sulfate proteoglycan core protein content of glomerular epithelial cells. 213 58


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