The podocyte slit-diaphragm: target of anti-nephrin antibodies

PURPOSE OF REVIEW: This review is prompted by substantial new information on the composition and structure of the podocyte slit-diaphragm and the identification of anti-nephrin antibodies in patients with acquired diseases of the glomerular podocyte, including steroid-sensitive nephrotic syndrome of childhood, minimal change disease and some cases of primary focal and segmental glomerulosclerosis (FSGS). RECENT FINDINGS: New methodologies including multi-epitope affinity purification, high resolution proteomics and cryo-electron tomography reveal that the slit-diaphragm consists of a multi-layered fishnet-like structure made up by nephrin and neph1 homodimers as well as several co-assembled proteins with signaling properties. Insights from clinical studies and experimental models support the concept that pathogenic antibodies engaging the extracellular domain of nephrin disrupt the integrity of the slit-diaphragm and signal changes to the podocyte cytoskeleton that lead to foot process effacement and proteinuria. SUMMARY: These findings raise several questions to be answered experimentally, including the nephrin epitopes targeted by the antibodies and the way in which they alter the slit-diaphragm and podocyte architecture and induce nephrin endocytosis. They also highlight the need for a reliable and widely available assay for anti-nephrin antibodies, which would have diagnostic and therapeutic impact on diagnosis, prognosis and therapy.