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      Increased Glomerular Cell Heparan Sulfates in vitro by Ciclosporin A: A Possible Explanation of Its Beneficial Effect in Idiopathic Nephrotic Syndrome

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          Background/Aim: In idiopathic nephrotic syndrome (INS), ciclosporin A (CsA) was shown to decrease proteinuria, an effect explained by its immunologic and hemodynamic actions. In order to determine whether CsA could have a direct action on glomerular cells, we studied the effect of CsA on glomerular cells in vitro, particularly on glycosaminoglcycans (GAG) and heparan sulfates (HS) which are decreased in INS patients. Methods: Human glomerular epithelial cells and rat mesangial cells were cultured at various concentrations of CsA. HS were quantified using a cationic membrane after metabolic labeling. Results: Mesangial cell GAG and HS and epithelial cell HS increased significantly when cells were cultured with CsA. For both cell types this increase was prevailing on the secreted fraction of HS in comparison with the cellular fraction. CsA induced also an increase in cellular cAMP levels, but the effect of CsA was not transduced via a cAMP pathway. Conclusions: CsA is able to increase glomerular GAG and HS in vitro. As this effect of CsA was the opposite effect on glomerular cells to the effect of plasma from INS patients, we conclude that this direct action of CsA on glomerular cells could explain in part the effect of this drug in decreasing proteinuria in INS.

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          A critique of the overfill hypothesis of sodium and water retention in the nephrotic syndrome.

          Recent reviews have claimed that the majority of patients with the nephrotic syndrome have plasma volume expansion (that is, they are overfilled). Here we attempt to re-establish balance to the debate on body fluid volume status in nephrotic patients by: (a) discussing the conflicting literature on plasma volume measurements in the nephrotic syndrome; (b) providing alternate explanations for data purporting to support an overfill hypothesis in the nephrotic syndrome; (c) emphasizing secondary neurohumoral responses that support underfilling at least as frequently as overfilling; and (d) emphasizing the clinical importance of fluid assessment in the individual patient with the nephrotic syndrome particularly in relation to diuretic use.
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            Therapeutic concentrations of cyclosporine A, but not FK506, increase P-glycoprotein expression in endothelial and renal tubule cells.

            The immunosuppressive drugs cyclosporine A (CsA) and tacrolimus (FK506) are extruded from cells by the multidrug resistance P-glycoprotein (P-gp), an efflux pump for drugs and xenobiotics, which may limit their therapeutic effectiveness and/or incidence of toxic side effects. In the present study, we investigated the effect of therapeutic concentrations of CsA and FK506 on the expression of P-gp in cultured endothelial and proximal tubule cells. P-gp expression in human arterial endothelial (HAEC) and rat proximal tubule cells (RPTC) was determined by immunoblotting and immunocytochemistry, and correlated with P-gp-mediated transport by measuring the intracellular accumulation of the fluorescent probe calcein. Following incubation of HAEC with therapeutic concentrations of 0.1 to 1.6 microM CsA up to seven days, P-gp expression increased in a time- and concentration-dependent manner, maximally to 291 +/- 42% of controls with 0.8 microM CsA for seven days. Similar effects of CsA were observed in RPTC. In contrast, therapeutic concentrations of FK506 (0.01 to 0.2 microM up to 7 days) did not change P-gp expression in either cell type, though at higher, supratherapeutic concentrations of FK506 (0.6 to 1.2 microM) P-gp expression was also increased. Immunocytochemistry revealed increased P-gp expression in the plasma membrane of HAEC and RPTC treated with 0.8 microM CsA, which was reflected by a decrease of P-gp-mediated accumulation of calcein in both cell types. The data suggest that the induction of P-gp expression in HAEC and RPTC at concentrations of CsA or FK506 above 0.5 microM is part of the protective answer of cells to toxic concentrations of the drugs and could therefore interfere with the therapeutic effectiveness of CsA in vivo.
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              Minimal change nephropathy: An electrochemical disorder of the glomerular membrane


                Author and article information

                S. Karger AG
                25 May 2001
                : 88
                : 2
                : 156-162
                Departments of aPediatrics and bObstetrics and Gynecology, University Hospital of Geneva, Switzerland
                45977 Nephron 2001;88:156–162
                © 2001 S. Karger AG, Basel

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                Figures: 3, References: 54, Pages: 7
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