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      The Charge for Going by Foot: Modifying the Surface of Podocytes

      Cardiorenal Medicine

      S. Karger AG

      Podocyte, Charge alteration, Glomerular filtration, Glomerular disease

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          The podocyte is a highly differentiated cell which forms a crucial component of the glomerular filtration barrier. It maintains a large filtration surface through the slit membranes and counteracts the distension of the glomerular basement membrane. The podocyte is covered with an anionic glycocalyx believed to be important in the maintenance of foot process structures, but the mechanisms of the cellular interaction between podocyte charge and its function are not clearly understood. It has been speculated that the charge selectivity of the glomerular barrier is influenced by angiotensin II. In experimental models of glomerular nephropathy neutralization of the polyanionic surface with polycations causes a retraction of podocyte foot processes. The effect of polycations is energy and Ca<sup>2+</sup> dependent and results in tyrosine kinase induced phosphorylation of proteins of the foot processes. Charge alterations of the podocyte seem also associated with proteinuria in several human glomerular diseases such as membranous or diabetic nephropathy. The knowledge of the interaction between charge and podocyte function might offer new strategies in the treatment of glomerular diseases.

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          Most cited references 2

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          The tight junction protein ZO-1 is concentrated along slit diaphragms of the glomerular epithelium

          The foot processes of glomerular epithelial cells of the mammalian kidney are firmly attached to one another by shallow intercellular junctions or slit diaphragms of unknown composition. We have investigated the molecular nature of these junctions using an antibody that recognizes ZO-1, a protein that is specific for the tight junction or zonula occludens. By immunoblotting the affinity purified anti-ZO-1 IgG recognizes a single 225-kD band in kidney cortex and in slit diaphragm-enriched fractions as in other tissues. When ZO-1 was localized by immunofluorescence in kidney tissue of adult rats, the protein was detected in epithelia of all segments of the nephron, but the glomerular epithelium was much more intensely stained than any other epithelium. Among tubule epithelia the signal for ZO-1 correlated with the known fibril content and physiologic tightness of the junctions, i.e., it was highest in distal and collecting tubules and lowest in the proximal tubule. By immunoelectron microscopy ZO-1 was found to be concentrated on the cytoplasmic surface of the tight junctional membrane. Within the glomerulus ZO-1 was localized predominantly in the epithelial foot processes where it was concentrated precisely at the points of insertion of the slit diaphragms into the lateral cell membrane. Its distribution appeared to be continuous along the continuous slit membrane junction. When ZO-1 was localized in differentiating glomeruli in the newborn rat kidney, it was present early in development when the apical junctional complexes between presumptive podocytes are composed of typical tight and adhering junctions. It remained associated with these junctions during the time they migrate down the lateral cell surface, disappear and are replaced by slit diaphragms. The distribution of ZO-1 and the close developmental relationship between the two junctions suggest that the slit diaphragm is a variant of the tight junction that shares with it at least one structural protein and the functional property of defining distinctive plasmalemmal domains. The glomerular epithelium is unique among renal epithelia in that ZO-1 is present, but the intercellular spaces are wide open and no fibrils are seen by freeze fracture. The presence of ZO-1 along slit membranes indicates that expression of ZO-1 alone does not lead to tight junction assembly.
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            Molecular cloning, expression, and characterization of podocalyxin-like protein 1 from rabbit as a transmembrane protein of glomerular podocytes and vascular endothelium.

            Podocytes are responsible in part for maintaining the size and charge filtration characteristics of the glomerular filter. The major sialoprotein of the podocyte foot process glycocalyx is a 140-kDa sialoprotein named podocalyxin. Monoclonal antibodies raised against isolated rabbit glomeruli that recognized a podocalyxin-like protein base upon size, Alcian blue staining, wheat germ agglutinin binding, and distribution in renal cortex were used to expression clone cDNAs from a rabbit glomerular library. On Northern blot the cDNAs hybridized to a 5.5-kilobase pair transcript predominantly present in glomerulus. The overlapping cDNAs spanned 5,313 base pairs that contained an open reading frame of 1,653 base pairs and were not homologous with a previously described sequence. The deduced 551-amino acid protein contained a putative 21-residue N-terminal signal peptide and a 26-amino acid transmembrane region. The mature protein has a calculated molecular mass of 55 kDa, an extracellular domain that contains putative sites for N- and O-linked glycosylation, and a potential glycosaminoglycan attachment sites. The intracellular domain contains potential sites for phosphorylation. Processing of the full-length coding region in COS-7 cells resulted in a 140-kDa band, suggesting that the 55-kDa core protein undergoes extensive post-translational modification. The relationship between the cloned molecule and the monoclonal antibodies used for cloning was confirmed by making a fusion protein that inhibited binding of the monoclonal antibodies to renal cortical tissue sections and then raising polyclonal antibodies against the PCLP1 fusion protein that also recognized glomerular podocytes and endothelial cells in tissue sections in a similar distribution to the monoclonal antibodies. We conclude that we have cloned and sequenced a novel transmembrane core glycoprotein from rabbit glomerulus, which has many of the characteristics of podocalyxin. We have named this protein podocalyxin-like protein 1.

              Author and article information

              Nephron Exp Nephrol
              Cardiorenal Medicine
              S. Karger AG
              April 1998
              20 March 1998
              : 6
              : 2
              : 98-103
              Department of Medicine, Division of Nephrology, University of Freiburg, Germany
              20511 Exp Nephrol 1998;6:98–103
              © 1998 S. Karger AG, Basel

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              References: 35, Pages: 6
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