During development, glomerular visceral epithelial cells, or podocytes, undergo extensive morphologic changes necessary for the creation of the glomerular filter. These changes include formation of interdigitating foot processes, replacement of tight junctions with slit diaphragms, and the concomitant opening of filtration slits. It was postulated previously and confirmed recently that podocalyxin, a sialomucin, plays a major role in keeping the urinary space open by virtue of the physicochemical properties of its highly negatively charged ectodomain. By a cell aggregation assay, the expression level of podocalyxin correlated closely with the anti-adhesion effect. Treatment of the cells with sialidase reversed the inhibitory effect of podocalyxin, indicating that sialic acid residue is required for inhibition of cell adhesion. In addition to its ectodomain, the highly conserved cytoplasmic tail of podocalyxin may contribute to the unique organization of podocytes. By immunocytochemistry, it was shown that two cytosolic adaptor proteins, Na(+)/H(+)-exchanger regulatory factor 2 (NHERF2) and ezrin, colocalize with podocalyxin along the apical plasma membrane of podocytes, where they form a co-immunoprecipitable complex. Moreover, the podocalyxin/NHERF2 /ezrin complex interacts with the actin cytoskeleton, and this interaction is disrupted in pathologic conditions associated with changes in the foot processes, indicating its importance in maintaining the unique organization of this epithelium. Further studies will be needed to identify the signaling molecules responsible for the regulation of this complex in podocyte damage.