Podocyte phenotypes as defined by expression and distribution of GLEPP1 in the developing glomerulus and in nephrotic glomeruli from MCD, CNF, and FSGS. A dedifferentiation hypothesis for the nephrotic syndrome.

Glomerular epithelial protein 1 (GLEPP1) is a podocyte receptor membrane protein tyrosine phosphatase located on the apical cell membrane of visceral glomerular epithelial cell (VGEC) foot processes. Double label immunofluorescence, immunoelectron microscopy, and peroxidase immunohistochemistry were used to map the GLEPP1 distribution in the developing glomerulus and in minimal-change nephropathy (MCN), congenital nephrotic syndrome of the Finnish type, and focal-segmental glomerulosclerosis (FSGS). In MCN GLEPP1 was shifted away from the glomerular basement membrane on the apical cell membrane of effaced foot processes. These data are compatible with the previously suggested concept that MCN can be considered a form of dedifferentiation of the podocyte phenotype. Similarly, changes seen in congenital nephrotic syndrome of the Finnish type can be considered a consequence of failure to complete normal podocyte development. In FSGS glomeruli GLEPP1 was frequently absent from VGECs, even when no sclerosis was detectable in that glomerulus. Therefore, in FSGS, VGECs may lose GLEPP1, and this loss appears to occur in the absence of scarring and may, therefore, precede the scarring process. We speculate that a changed VGEC phenotype that does not express GLEPP1 might have properties similar to the early undifferentiated VGEC developmental phenotype. GLEPP1 distribution pattern and absence from glomeruli of individuals with nephrotic syndrome may, therefore, represent a useful phenotypic marker.