Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There are currently no effective therapies for progressive fibrotic diseases. Recent evidence has implicated overproduction of transforming growth factor-beta1 (TGF-beta1) as a major cause of tissue fibrosis. Furthermore, this evidence implies that inhibitors of TGF-beta1 may be clinically useful as antifibrotic agents. The proteoglycan decorin is a known inhibitor of TGF-beta1. In a rat model of glomerulonephritis we have shown that fibrosis is mediated by TGF-beta1. We report here that transfer of decorin cDNA into rat skeletal muscle increases the amount of decorin messenger RNA and protein present in skeletal muscle and decorin present in kidney, where it has a marked therapeutic effect on fibrosis induced by glomerulonephritis. Transfected glomerulonephritic rats showed a significant reduction in levels of glomerular TGF-beta1 mRNA and TGF-beta1 protein, extracellular matrix accumulation and proteinuria. These results demonstrate the potential of gene therapy as a novel treatment for fibrotic diseases caused by TGF-beta1.
 ...
PMID:Gene therapy by skeletal muscle expression of decorin prevents fibrotic disease in rat kidney. 859 51

Proteoglycans are an important component of the extracellular matrix, and are thought to play multiple roles not only in kidney remodeling, but also in regulating glomerular permeability, and in modulating the activity of other cytokines and growth factors. The aim of this study was to examine the gene expressions of proteoglycan core proteins in hypertensive rat kidneys, and their modulation by AT1 receptor antagonist. SHRSP/Izm rats and normotensive control WKY/Izm rats on a normal salt diet were treated with or without the AT1 receptor antagonist candesartan cilexetil (1 mg/kg/day) from 10 weeks to 22 weeks. At the end of the treatment period, renal tissue was excised, and gene expressions of the proteoglycan core proteins versican, perlecan, decorin, and biglycan were examined by Northern blot analysis and RT-PCR. Treatment with candesartan cilexetil caused significant decreases in blood pressure and amelioration of proteinuria and renal histological scores in the SHRSP/Izm rats. Compared to WKY/Izm rats, expression of biglycan mRNA showed a small increase in SHRSP/Izm rats which did not attain statistical significance. On the other hand, treatment with candesartan caused significant reductions in biglycan and decorin mRNA in the SHRSP/Izm rats. In contrast, the level of versican mRNA appeared to be increased after candesartan treatment. These results suggest that treatment with AT1 receptor antagonist was associated with diverse changes in renal proteoglycan gene expression in SHRSP/Izm rats. These changes could contribute to the beneficial effects of AT1 receptor antagonist on tissue remodeling and inhibition of disease progression in hypertensive rat kidneys.
 ...
PMID:Effects of AT1 receptor antagonist on proteoglycan gene expression in hypertensive rats. 1132 76

We investigated the effects of age on adriamycin-induced nephropathy in mice. Disease was produced by a single intravenous injection of adriamycin (doxorubicin hydrochloride) (AD, 20 mg/kg) in female Balb/C mice of 5 and 12 weeks of age. Urinary protein and transforming growth factor (TGF)-beta1 concentrations were measured and the extent of glomerular sclerosis/hyalinosis and tubulointerstitial fibrosis was scored. Decorin and fibromodulin expression was quantified using reverse transcription-polymerase chain reaction. In normal mouse kidneys, urinary TGF-beta1 excretion and decorin and fibromodulin mRNA did not change with age. When nephropathy was induced, the 12-week-old group demonstrated significantly greater proteinuria, urinary TGF-beta1 excretion, and interstitial fibrosis ( P<0.05) than the 5-week-old group. Decorin and fibromodulin expression was not significantly different between the groups. We conclude that 12-week-old mice develop more severe nephropathy than the younger mice following administration of the equivalent weight-based dose of AD. Decorin and fibromodulin do not play a role in this difference.
 ...
PMID:Age-related differences in adriamycin-induced nephropathy. 1513 73

This article describes the possible role of the endothelial cell-surface coat, containing proteoglycans (PGs) with connected glycosaminoglycans (GAGs), in maintaining glomerular permselectivity. Primary human glomerular endothelial cells (HGEC) in culture were treated with the nephrosis-inducing agent puromycin aminonucleoside (PAN). Analysis was made by TaqMan real-time PCR, Western blot analysis, and by metabolic labeling with [(35)S]sulfate. The HGECs express several PGs: syndecan, versican, glypican, perlecan, decorin, and biglycan, which may contribute to the glomerular charge barrier. PAN treatment downregulated both the protein expression (by 25%) and the mRNA expression (by 37 +/- 6%, P < 0.001, n = 8) of versican compared with control. Transferases important for chondroitin and heparan sulfate biosynthesis were also significantly downregulated by PAN, resulting in less sulfate groups, shorter GAG chains, and reduced PG net-negative charge. Moreover, analysis of the cell media after PAN treatment revealed a reduced content of [(35)S]sulfate-labeled PGs (40% of control). We conclude that PAN may cause proteinuria by affecting the endothelial cell-surface layer and not only by disrupting the foot process arrangement of the podocytes. Thus the endothelium may be a more important component of the glomerular barrier than hitherto acknowledged.
 ...
PMID:Primary human glomerular endothelial cells produce proteoglycans, and puromycin affects their posttranslational modification. 1558 70

Although deficiency of the small leucine-rich proteoglycan decorin aggravates diabetic nephropathy in mice, the precise mechanisms of action are not fully understood. In the present study we used decorin-deficient mice (Dcn(-/-)) to further elucidate the molecular mechanisms involved in the protective action of decorin in diabetes. We discovered that streptozotocin-induced diabetes in Dcn(-/-) mice led to increased proteinuria associated with enhanced cyclin-dependent kinase inhibitor p27Kip1 in podocytes and tubular epithelial cells. Furthermore, lack of decorin increased the rate of apoptosis and caused overexpression of the IGF-IR in tubular epithelial cells of diabetic kidneys. In vitro experiments using human proximal renal epithelial cells showed that recombinant decorin was bound to the IGF-IR and protected against high glucose-mediated apoptosis. Furthermore, overexpression of TGFbeta1 and CTGF triggered by decorin deficiency resulted in enhanced accumulation of extracellular matrix in diabetic kidneys. Notably, diabetic Dcn(-/-) kidneys revealed marked upregulation of the proinflammatory proteoglycan biglycan and enhanced infiltration of mononuclear cells. Collectively, our results indicate that decorin is a protective agent during the development of diabetic nephropathy. Future therapeutic approaches that would either enhance the endogenous production of decorin or deliver recombinant decorin to the diseased kidney might improve the outcome of patients with diabetic nephropathy.
 ...
PMID:Decorin deficiency in diabetic mice: aggravation of nephropathy due to overexpression of profibrotic factors, enhanced apoptosis and mononuclear cell infiltration. 2008 46