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

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).

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.

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.