The slit diaphragm bridging the neighboring foot processes functions as a final barrier of glomerular capillary wall for preventing the leak of plasma proteins into primary urine. It is now accepted that the dysfunction of the sit diaphragm contributes to the development of proteinuria in several glomerular diseases. Nephrin, a gene product of NPHS1 , a gene for a congenital nephrotic syndrome of Finnish type, constitutes an extracellular domain of the slit diaphragm. Podocin was identified as a gene product of NPHS2 , a gene for a familial steroid-resistant nephrotic syndrome of French. Podocin binds the cytoplasmic domain of nephrin. After then, CD2 associated protein, NEPH1 and transient receptor potential-6 were also found as crucial molecules of the slit diaphragm. In order to explore other novel molecules contributing to the development of proteinuria, we performed a subtraction hybridization assay with a normal rat glomerular RNA and a glomerular RNA of rats with a puromycin aminonucleoside nephropathy, a mimic of a human minimal change type nephrotic syndrome. Then we have found that synaptic vesicle protein 2B, ephrin-B1 and neurexin were already downregulated at the early stage of puromycin aminonucleoside nephropathy, and that these molecules were localized close to nephrin. It is conceivable that these molecules are the slit diaphragm associated molecules, which participate in the regulation of the barrier function. These molecules could be targets to establish a novel therapy for nephrotic syndrome. Core tip: The slit diaphragm located between neighboring foot processes of a glomerular podocyte functions as a final barrier to retain plasma proteins. Recently several molecules such as nephrin and podocin were identified as functional molecules of the slit diaphragm. However, the precise molecular compositions of the slit diaphragm are still unclear and the mechanism regulating its barrier function is not fully understood yet. Recently we have reported that synaptic vesicle protein 2B, ephrin-B1 and neurexin are expressed in podocyte and the decreased function of these molecules participates in the initiation of proteinuria. These molecules could be targets for a novel therapy for proteinuria.Fukusumi Y, Miyauchi N, Hashimoto T, Saito A, Kawachi H. Therapeutic target for nephrotic syndrome: Identification of novel slit diaphragm associated molecules.