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)

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

Introduction: Proteinuria contributes to progression of renal damage, partly by complement activation on proximal tubular epithelial cells. By pattern recognition, properdin has shown to bind to heparan sulfate proteoglycans on tubular epithelium and can initiate the alternative complement pathway (AP). Properdin however, also binds to C3b(Bb) and properdin binding to tubular cells might be influenced by the presence of C3b(Bb) on tubular cells and/or by variability in properdin proteins in vitro. In this study we carefully evaluated the specificity of the properdin - heparan sulfate interaction and whether this interaction could be exploited in order to block alternative complement activation. Methods: Binding of various properdin preparations to proximal tubular epithelial cells (PTEC) and subsequent AP activation was determined in the presence or absence of C3 inhibitor Compstatin and properdin inhibitor Salp20. Heparan sulfate proteoglycan dependency of the pattern recognition of properdin was evaluated on PTEC knocked down for syndecan-1 by shRNA technology. Solid phase binding assays were used to evaluate the effectivity of heparin(oids) and recombinant Salp20 to block the pattern recognition of properdin. Results: Binding of serum-derived and recombinant properdin preparations to PTECs could be dose-dependently inhibited (P < 0.01) and competed off (P < 0.01) by recombinant Salp20 (IC50: ~125 ng/ml) but not by Compstatin. Subsequent properdin-mediated AP activation on PTECs could be inhibited by Compstatin (P < 0.01) and blocked by recombinant Salp20 (P < 0.05). Syndecan-1 deficiency in PTECs resulted in a ~75% reduction of properdin binding (P = 0.057). In solid-phase binding assays, properdin binding to C3b could be dose-dependently inhibited by recombinant Salp20> heparin(oid) > C3b. Discussion: In this study we showed that all properdin preparations recognize heparan sulfate/syndecan-1 on PTECs with and without Compstatin C3 blocking conditions. In contrast to Compstatin, recombinant Salp20 prevents heparan sulfate pattern recognition by properdin on PTECs. Both complement inhibitors prevented properdin-mediated C3 activation. Binding of properdin to C3b could also be blocked by heparin(oids) and recombinant Salp20. This work indicates that properdin serves as a docking station for AP activation on PTECs and a Salp20 analog or heparinoids may be viable inhibitors in properdin mediated AP activation.
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PMID:Properdin Pattern Recognition on Proximal Tubular Cells Is Heparan Sulfate/Syndecan-1 but Not C3b Dependent and Can Be Blocked by Tick Protein Salp20. 3284 63