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)

Anecdotal evidence links silicone gel breast implants with the development of autoimmune connective tissue disease in women. To investigate whether silicone gel is capable of directly inducing and/or enhancing the development of autoimmune disease, female BALB/cAnPt (BALB/c) and New Zealand Black (NZB) mice were injected subcutaneously with silicone gel, pristane, a nonmetabolizable substance that can cause plasmacytomas in BALB/c and NZB mice, or saline and monitored for the development of glomerulonephritis and autoantibody production. NZB, but not BALB/c, mice spontaneously develop autoantibodies and an autoimmune hemolytic anemia by 12 months of age. Over a period of 10 months, biweekly screening for proteinuria revealed increases in urinary protein in NZB mice that received multiple injections of either silicone gel or pristane. In contrast, urinary protein was unaffected in identically treated BALB/c mice. Although, silicone gel had no effect on serum titers of antierythrocyte antibodies in NZB mice, the hematocrits were significantly decreased. Moreover, silicone gel both increased the concentration of IgM anti-type I collagen antibodies and skewed the immunofluorescent staining pattern of serum autoantibodies on HEp-2 cells. In contrast, silicone gel failed to induce the production of anti-erythrocyte or antinuclear antibodies in BALB/c mice and induced only slight increases in IgG anti-type I collagen antibodies. These results suggest that silicone gel can exacerbate the development of autoimmune disease in autoimmune NZB mice, but fails to induce disease in normal BALB/c mice. This is consistent with several epidemiological studies failing to demonstrate an increase in the incidence of autoimmune disease in women with breast implants. However, because silicone gel was able to exacerbate autoimmune disease in NZB mice, it may play a similar role in the development of autoimmune disease in a small percentage of women who are genetically susceptible to such diseases.
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PMID:Silicone gel enhances the development of autoimmune disease in New Zealand black mice but fails to induce it in BALB/cAnPt mice. 964 28

Multiple injections with a mouse monoclonal anti-rat Thy-1 antibody (five times, at weekly intervals) induced marked glomerular sclerotic lesions which are characterized by adhesion of glomerular capillaries to Bowman's capsule and persistent proteinuria in rats. Abnormal production of type I collagen and increased accumulation of type IV collagen and fibronectin were observed in these glomeruli. The glomerular expression of mRNA for these matrix components and transforming growth factor-beta1 (TGF-beta1) were markedly increased at 4 days after the last injections with anti-Thy-1 antibody, but decreased to below the levels of control rats at 5 weeks. This may be down-regulation of mRNA in mesangial cells. The glomerular sclerotic lesions were not progressive but the process of glomerular healing seemed to be retarded. The proteinuria and the glomerular adhesion were irreversible.
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PMID:Long-term observation of glomerulonephritis induced by multiple injections with anti-Thy-1 antibody in rats. 970 Oct 10

Leptin is a small peptide hormone that is mainly, but not exclusively, produced in adipose tissue. The circulating leptin concentration therefore directly reflects the amount of body fat. Leptin was identified through positional cloning of the obese (ob) gene, which is mutated in the massively obese ob/ob mouse, and it has a pivotal role in regulating food intake and energy expenditure. It binds to the so-called long receptor (Ob-Rb) in the hypothalamus and regulates food intake through the release of other neurotransmitters. Moreover, leptin exerts several other important metabolic effects on peripheral tissue, including modification of insulin action, induction of angiogenesis, and modulation of the immune system. As a small peptide, leptin is cleared principally by the kidney. Not surprisingly, serum leptin concentrations are increased in patients with chronic renal failure and those undergoing maintenance dialysis. Whether the hyperleptinemia of chronic renal failure contributes to some uremic manifestations, such as anorexia and weight loss, requires additional investigation. The kidney expresses abundant concentrations of the truncated isoform of the leptin receptor Ob-Ra, but only a small amount of the full-length receptor Ob-Rb. We recently discovered that leptin has direct effects on renal pathophysiological characteristics. Both cultured glomerular endothelial cells and mesangial cells obtained from the diabetic db/db mouse possess the Ob-Ra receptor, but whether biological effects of leptin are transduced through this receptor remains unknown. In glomerular endothelial cells, leptin stimulates cellular proliferation, transforming growth factor-beta1 (TGF-beta1) synthesis, and type IV collagen production. Conversely, in mesangial cells, leptin upregulates synthesis of the TGF-beta type II receptor, but not TGF-beta1, and stimulates glucose transport and type I collagen production through signal transduction pathways involving phosphatidylinositol-3-kinase. These data suggest that leptin triggers a paracrine interaction in which glomerular endothelial cells secrete TGF-beta, to which sensitized mesangial cells may respond. Both cell types increase their expression of extracellular matrix in response to leptin. Infusion of leptin into normal rats for 3 weeks fosters the development of focal glomerulosclerosis and proteinuria. Additional previously described direct and indirect effects of leptin on the kidney include natriuresis, increased sympathetic nervous activity, and stimulation of reactive oxygen species. These findings collectively suggest that the kidney is not only a site of leptin metabolism, but also a target organ for leptin action in pathophysiological states.
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PMID:Leptin and renal disease. 1177 95

It has been postulated that protein filtered through glomeruli activates tubular epithelial cells, which secrete vasoactive and inflammatory substances including chemokines, leading to tubulointerstitial renal injury. The present study was designed to investigate the role of monocyte chemoattractant protein-1 (MCP-1) in this process and to evaluate the effectiveness of a kidney-targeted gene transfer technique using hydrodynamic pressure. Naked plasmid encoding 7ND (an MCP-1 antagonist) or a control plasmid was introduced into the left kidney of rats. Three days after gene transfer (day 0), intraperitoneal administration of bovine serum albumin (10 mg/g body wt per day) was started and continued for 14 or 21 d. RT-PCR showed that 7ND mRNA was expressed only in the gene-transfected kidney. Immunostaining showed that 7ND protein was localized in the interstitial cells. Macrophage infiltration was significantly reduced in the left kidney of rats treated with 7ND on days 14 and 21. In the right kidney, such effects were not observed. 7ND also attenuated tubular damage and decreased the number of apoptotic cells. Computer-assisted analysis revealed that the areas positively stained for alpha-smooth muscle actin (alpha SMA), fibronectin-EDA, type I collagen, and collagen fibrils were significantly reduced in the 7ND-treated kidney on day 21. Furthermore, 7ND gene therapy significantly reduced MCP-1 and TGF-beta 1 mRNA expression. These results demonstrate that MCP-1 plays an important role in the development of tubulointerstitial inflammation, tubular damage, and fibrosis induced by proteinuria. The fact that 7ND gene therapy had little effect on the contralateral kidney indicates that 7ND acted locally. This strategy may have a potential usefulness as a gene therapy against tubulointerstitial renal injury.
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PMID:Anti-monocyte chemoattractant protein-1 gene therapy attenuates renal injury induced by protein-overload proteinuria. 1276 Dec 50

Diabetic nephropathy is characterized by progressive loss of renal function, persistent proteinuria, and relentless accumulation of extracellular matrix leading to glomerulosclerosis and interstitial fibrosis. This study investigated the potential effects of long-term expression of exogenous hepatocyte growth factor (HGF) on normal and diabetic kidneys. Intravenous injection of human HGF gene via naked plasmid vector resulted in abundant HGF protein specifically localized in renal glomeruli, despite an extremely low level of transgene mRNA in the kidney. In uninephrectomized mice made diabetic with streptozotocin, delivery of exogenous HGF gene ameliorated the progression of diabetic nephropathy. HGF attenuated urine albumin and total protein excretion in diabetic mice. Exogenous HGF also mitigated glomerular mesangial expansion, reduced fibronectin and type I collagen deposition, and prevented interstitial myofibroblast activation. In addition, HGF prevented kidney cells from apoptotic death in the glomeruli and tubulointerstitium. Moreover, expression of HGF inhibited renal expression of TGF-beta1 and reduced urine level of TGF-beta1 protein. Therefore, despite the effects of HGF on diabetic nephropathy being controversial, these observations suggest that supplementation of HGF is beneficial in ameliorating diabetic renal insufficiency in mice.
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PMID:Intravenous administration of hepatocyte growth factor gene ameliorates diabetic nephropathy in mice. 1546 68

Although proteinuria is a predictor of renal outcome, it is also an accelerator of disease progression through renal parenchymal damage such as interstitial fibrosis. Therefore, to elucidate the genetic components contributing to collagen deposition by proteinuria, we employed a strategy to map genetic loci that influence the phenotype in mice that present high or low type I collagen (COLI) deposition in the kidney during proteinuria. Such COLI deposition in 129S1/svImJ and C57BL/6J inbred mouse strains differs most significantly among 9 tested inbred strains. We conducted a quantitative trait loci (QTL) analysis of 120 (129S1/svImJ x C57BL/6J) F1 x 129S1/svImJ backcross mice loaded with bovine serum albumin for 6 weeks to yield proteinuria and cause renal parenchymal damage. COLI deposition in the kidney during proteinuria was influenced by one suggestive QTL (logarithm of odds 2.84) that accounted for 10.2% of the total variance, and its peak position was located at 81.7 cM near D2Mit224 on Chr 2. Progenies with a homologous 129S1/svImJ allele showed more COLI deposition in the kidney than those with heterozygous alleles, suggesting that the 129S1/svIlmJ allele is recessive. Although further studies elucidating candidate genes underlying this region are necessary, such information will provide a chance to unravel the genetics of renal fibrogenesis.
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PMID:[Quantitative trait loci analysis for type I collagen deposition in the kidney during urinary protein load]. 1818 27

The progression of chronic kidney disease is a complex process influenced by genetic factors. Proteinuria is a predictor of functional deterioration and an accelerator of disease progression through renal parenchymal damage and interstitial fibrosis. To determine genetic components that might mediate renal fibrosis due to proteinuria, we mapped loci influencing the phenotype of two mouse strains differing in proteinuria-induced renal type I collagen (COLI) deposition. Collagen I deposition in 129S1/svImJ and C57BL/6J mice differs significantly among tested strains. We backcrossed 120 hemi-nephrectomized (129S1/svImJ x C57BL/6J) F1 x 129S1/svImJ backcrossed mice loaded with bovine serum albumin giving rise to proteinuria and renal COLI deposition. Quantitative trait loci (QTL) mapping was performed and our analysis identified one suggestive linkage for renal COLI deposition peaking at 87 cM near D2Mit224 (logarithm of odds: 2.41) on Chr 2. In silico analysis uncovered nine candidate genes. Hence, although more studies are needed, these QTL provide an initial cue to subsequent gene discovery, which might help unravel the genetics of renal fibrosis.
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PMID:Mapping quantitative trait loci for proteinuria-induced renal collagen deposition. 1841 35

ICGN/Oa mice are used to study the pathophysiological mechanisms underlying proteinuria-induced chronic kidney disease (CKD). Recently, a mutation of tensin2 gene (Tns2) was suggested to be responsible for proteinuria in the inbred ICGN mice. We identified the wild-type (+/+), heterozygous (+/nep), and homozygous (nep/nep) ICGN/Oa mice by PCR assay. The homozygotes developed proteinuria, resulting in nephrotic syndrome (NS) as early as 5 weeks and CKD by 15 weeks. However, the heterozygotes did not show the symptoms of these renal failures. These results indicate that the homozygous tensin2 mutation is necessary for the ICGN/Oa mice to develop proteinuria-induced CKD. Furthermore, we examined the time course of tubulointerstitial fibrosis and the kinetics of tubular epithelial cells (TECs) in the ICGN/Oa mice using immunohistochemical and TUNEL assays. In the renal parenchyma of the five-week-old homozygotes, the expression of alpha-SMA and type I collagen were higher than those in the age-matched wild-type. Additionally, increased TEC proliferation was found at 5 weeks, and increased TEC apoptosis was by 15 weeks in the homozygotes. Tubulointerstitial fibrosis precedes TEC apoptosis in the proteinuria-induced CKD model mice, and that tubulointerstitial fibrosis may be the triggering event of the disease.
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PMID:Proteinuria-induced chronic kidney disease in the ICGN/Oa mice with a mutation of Tensin2 gene. 1928 29

Agents that inhibit glycation end products by reducing the carbonyl load from glycation and glycoxidation are an emerging pharmacologic approach to treat complications of diabetes. We previously demonstrated that antibodies generated to the glycoprotein keyhole limpet hemocyanin (KLH) can cross-link with reactive carbonyl residues on protein conjugates. Here, we immunized streptozotocin-induced diabetic rats with KLH to assess the capacity of the elicited antibodies to intercept carbonyl residues on glycated proteins and to mitigate glycation-related pathology. Compared with diabetic rats immunized with adjuvant alone, KLH-immunized diabetic rats had decreased levels of glycated peptides in sera and demonstrated a reduction in albuminuria, proteinuria, deposition of glycation end products in the kidney, and histologic damage. In vitro, low molecular weight glycated peptides from rat serum reacted with anti-KLH antibodies at a faster rate than normal IgG and selectively modified the lambda chains. The reaction products contained peptide sequences from type I collagen alpha chain, albumin, and LDL receptor-related protein. These adduction reactions were inhibited by free KLH and by reduction of glycated peptides with borohydride. In summary, these results suggest that inherent reactivity of Ig light chains provides a natural mechanism for the removal of cytotoxic glycation products. This reactivity can be augmented by glycoprotein-specific reactive immunization, a potential biopharmaceutical approach to glycation-related pathology.
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PMID:Reactive immunization suppresses advanced glycation and mitigates diabetic nephropathy. 1938 54

Recent clinical studies on chronic kidney disease (CKD) reported that renal dysfunction was a critical risk factor for cardiovascular events (CVE), which lead us to reconsider the effect of cardioprotective agents on the kidney. Glomerulonephritis, which is the major cause of CKD, is characterized by mesangial cell proliferation and extracellular matrix deposition. Nicorandil, a therapeutic drug for angina and acute heart failure, have been reported to show antiproliferative activity in mesangial cells. In this study, we first investigated the in vivo effects of nicorandil in anti-Thy1 nephritis rats. In male F344 rats, anti-Thy1 nephritis was induced by the injection of an anti-Thy1 antibody. From three days before induction, nicorandil (10, 30 mg/kg per day) was administered in the drinking water for 12 consecutive days. Anti-Thy1 nephritis resulted in a significant increase in proteinuria and glomerular mesangial cell proliferation. In nephritis rats, nicorandil (30 mg/kg per day) significantly suppressed increase in proteinuria, mesangial cell proliferation (the number of glomerular cell and glomerular area), and renal hypertrophy without affecting blood pressure. Nicorandil significantly prevented the overexpression of type I collagen, fibronectin, transforming growth factor (TGF)-beta, and platelet-derived growth factor (PDGF) mRNA. These results suggest that nicorandil may have renoprotective effects in mesangioproliferative glomerulonephritis.
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PMID:Nicorandil improves glomerular injury in rats with mesangioproliferative glomerulonephritis via inhibition of proproliferative and profibrotic growth factors. 1972 33


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