title: The structural and functional organization of the podocyte filtration slits is regulated by Tjp1/ZO-1.
abstract: Blood filtration in the kidney glomerulus is essential for physiological homeostasis. The filtration apparatus of the kidney glomerulus is composed of three distinct components: the fenestrated endothelial cells, the glomerular basement membrane, and interdigitating foot processes of podocytes that form the slit diaphragm. Recent studies have demonstrated that podocytes play a crucial role in blood filtration and in the pathogenesis of proteinuria and glomerular sclerosis; however, the molecular mechanisms that organize the podocyte filtration barrier are not fully understood. In this study, we suggest that tight junction protein 1 (Tjp1 or ZO-1), which is encoded by Tjp1 gene, plays an essential role in establishing the podocyte filtration barrier. The podocyte-specific deletion of Tjp1 down-regulated the expression of podocyte membrane proteins, impaired the interdigitation of the foot processes and the formation of the slit diaphragm, resulting in glomerular dysfunction. We found the possibility that podocyte filtration barrier requires the integration of two independent units, the pre-existing epithelial junction components and the newly synthesized podocyte-specific components, at the final stage in glomerular morphogenesis, for which Tjp1 is indispensable. Together with previous findings that Tjp1 expression was decreased in glomerular diseases in human and animal models, our results indicate that the suppression of Tjp1 could directly aggravate glomerular disorders, highlights Tjp1 as a potential therapeutic target.
authors.affiliation: Department of Biochemistry, School of Medicine, Dokkyo Medical University, Mibu-machi, Shimotsuga-gun, Tochigi, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Itoh
authors.affiliation: Department of Basic Biology, Educational and Research Center for Pharmacy, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakadate
authors.affiliation: Department of Biochemistry, School of Medicine, Dokkyo Medical University, Mibu-machi, Shimotsuga-gun, Tochigi, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Horibata
authors.affiliation: Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Taiji
authors.initials: T
authors.lastname: Matsusaka
authors.affiliation: Epithelial Cell Biology Laboratory, Institute of Molecular and Cell Biology (IMCB), Singapore, Singapore.
authors.forename: Jianliang
authors.initials: J
authors.lastname: Xu
authors.affiliation: Epithelial Cell Biology Laboratory, Institute of Molecular and Cell Biology (IMCB), Singapore, Singapore.
authors.forename: Walter
authors.initials: W
authors.lastname: Hunziker
authors.affiliation: Department of Biochemistry, School of Medicine, Dokkyo Medical University, Mibu-machi, Shimotsuga-gun, Tochigi, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sugimoto
mesh_terms: D000818:Animals; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D050533:Glomerular Basement Membrane / Q000378:metabolism; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D012079:Renal Circulation / Q000235:genetics*; D062826:Zonula Occludens-1 Protein / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D008565:Membrane Proteins; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein