Glomerular expression of nephrin is decreased in acquired human nephrotic syndrome

the eVacement of foot processes represents a simpliBackground. Nephrin recently has been identified as a fication of architecture which demands massive remodputative adhesion molecule, expressed in the glomer- elling of the podocyte intercellular junction, the slit ulus, in which mutations cause congenital nephrotic diaphragm. syndrome of Finnish type. We sought to determine The molecular composition of the podocyte cell‐mawhether expression of nephrin is altered in human trix adhesion complexes has been largely determined glomeruli in patients with acquired nephrotic in recent years, but the composition of the slit diasyndrome. phragm remains surprisingly obscure. It contains the Methods. We performed PCR amplification of nephrin a-splice variant of ZO-1 [3], a protein which in the cDNA, using cDNA previously prepared from single a+ form is a normal constituent of tight junctions. human glomeruli plucked fresh from the surface of However, ultrastructurally and functionally, the slit human renal biopsies. We had available four cases of diaphragm is not a tight junction. Other tight junction nephrotic syndrome (one membranous, three minimal proteins such as cingulin [4] and occludin [5] are not change) and six normal controls. PCR product quant- present, and no other slit diaphragm-associated molecitation was by gel densitometry, confirmed by enzyme- ule has been identified. linked immunosorbent assay using a specific oligonu- The recent identification and sequencing of nephrin cleotide probe. Results were corrected for reaction has, therefore, provoked considerable interest [6 ]. A eYciency and glomerular cellularity by expression as a mutation in the gene for this protein was found to be ratio to levels of the ‘housekeeping gene’ glyceral- the underlying abnormality in the congenital nephrotic dehyde phosphate dehydrogenase. syndrome of Finnish type, where the glomerular podoResults. Glomerular levels of nephrin mRNA are signi- cytes fail to make normal foot processes or slit diaficantly decreased in cases of minimal change nephrotic phragms. Nephrin mRNA is expressed in normal syndrome. An apparent reduction was also seen in the kidneys, and has been localized by in situ hybridization single case of membranous nephropathy which was to the glomerular podocytes of a single human embryo available for study. [6 ]. Sequence analysis suggests that it is a novel Conclusions. Abnormalities of nephrin expression transmembrane adhesion molecule of the immunoglobappear to be associated with acquired as well as ulin superfamily and, therefore, one might speculate congenital causes of human nephrotic syndrome. that it could be a slit diaphragm component.