title: SIRPα interacts with nephrin at the podocyte slit diaphragm.
abstract: The slit diaphragm (SD) is an intercellular junction between renal glomerular epithelial cells (podocytes) that is essential for permselectivity in glomerular ultrafiltration. The SD components, nephrin and Neph1, assemble a signaling complex in a tyrosine phosphorylation dependent manner, and regulate the unique actin cytoskeleton of podocytes. Mutations in the NPHS1 gene that encodes nephrin cause congenital nephrotic syndrome (CNS), which is characterized by the loss of the SD and massive proteinuria. Recently, we have identified the expression of the transmembrane glycoprotein signal regulatory protein α (SIRPα) at the SD. In the present study, we analyzed the expression of SIRPα in developing kidneys, in kidneys from CNS patients and in proteinuric rat models. The possibility that SIRPα interacts with known SD proteins was also investigated. SIRPα was concentrated at the SD junction during the maturation of intercellular junctions. In the glomeruli of CNS patients carrying mutations in NPHS1, where SD formation is disrupted, the expression of SIRPα as well as Neph1 and nephrin was significantly decreased, indicating that SIRPα is closely associated with the nephrin complex. Indeed, SIRPα formed hetero-oligomers with nephrin in cultured cells and in glomeruli. Furthermore, the cytoplasmic domain of SIRPα was highly phosphorylated in normal glomeruli, and its phosphorylation was dramatically decreased upon podocyte injury in vivo. Thus, SIRPα interacts with nephrin at the SD, and its phosphorylation is dynamically regulated in proteinuric states. Our data provide new molecular insights into the phosphorylation events triggered by podocyte injury.
authors: Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Japan.
authors: Yuko
authors: Y
authors: Kajiho
authors: Yutaka
authors: Y
authors: Harita
authors: Hidetake
authors: H
authors: Kurihara
authors: Shigeru
authors: S
authors: Horita
authors: Atsuko
authors: A
authors: Matsunaga
authors: Haruko
authors: H
authors: Tsurumi
authors: Shoichiro
authors: S
authors: Kanda
authors: Noriko
authors: N
authors: Sugawara
authors: Kenichiro
authors: K
authors: Miura
authors: Takashi
authors: T
authors: Sekine
authors: Seisuke
authors: S
authors: Hattori
authors: Motoshi
authors: M
authors: Hattori
authors: Takashi
authors: T
authors: Igarashi
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009404:Nephrotic Syndrome / Q000378:metabolism*; D010766:Phosphorylation; D050199:Podocytes / Q000378:metabolism*; D011485:Protein Binding; D011507:Proteinuria / Q000378:metabolism; D051381:Rats; D011971:Receptors, Immunologic / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
chemical_list: D000943:Antigens, Differentiation; D008565:Membrane Proteins; D011971:Receptors, Immunologic; C501920:SIRPA protein, human; C501924:Sirpa protein, rat; C113267:nephrin; D014443:Tyrosine