title: Wtip- and gadd45a-interacting protein dendrin is not crucial for the development or maintenance of the glomerular filtration barrier.
abstract: Glomerular podocyte cells are critical for the function of the renal ultrafiltration barrier. Especially, the highly specialized cell-cell junction of podocytes, the slit diaphragm, has a central role in the filtration barrier. This is highlighted by the fact that mutations in molecular components of the slit diaphragm, including nephrin and Cd2-associated protein (Cd2ap), result in proteinuric diseases in man. Dendrin is a poorly characterized cytosolic component of the slit diaphragm in where it interacts with nephrin and Cd2ap. Dendrin is highly specific for the podocyte slit diaphragm, suggesting that it has a dedicated role in the glomerular filtration barrier. In this study, we have generated a dendrin knockout mouse line and explored the molecular interactions of dendrin. Dendrin-deficient mice were viable, fertile, and had a normal life span. Morphologically, the glomerulogenesis proceeded normally and adult dendrin-deficient mice showed normal glomerular histology. No significant proteinuria was observed. Following glomerular injury, lack of dendrin did not affect the severity of the damage or the recovery process. Yeast two-hybrid screen and co-immunoprecipitation experiments showed that dendrin binds to Wt1-interacting protein (Wtip) and growth arrest and DNA-damage-inducible 45 alpha (Gadd45a). Wtip and Gadd45a mediate gene transcription in the nucleus, suggesting that dendrin may have similar functions in podocytes. In line with this, we observed the relocation of dendrin to nucleus in adriamycin nephropathy model. Our results indicate that dendrin is dispensable for the function of the normal glomerular filtration barrier and that dendrin interacts with Wtip and Gadd45a.
authors.affiliation: Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Patricia Q
authors.initials: PQ
authors.lastname: Rodriguez
authors.affiliation: Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden ; Department of Immunology, Genetic and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Liqun
authors.initials: L
authors.lastname: He
authors.affiliation: Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden ; Department of Immunology, Genetic and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Betsholtz
authors.affiliation: Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden ; Cardiovascular and Metabolic Disorders Program, Duke-NUS, Singapore.
authors.forename: Karl
authors.initials: K
authors.lastname: Tryggvason
authors.affiliation: Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Patrakka
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D056970:Co-Repressor Proteins; D003598:Cytoskeletal Proteins; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005919:Glomerular Filtration Rate / Q000502:physiology; D007678:Kidney Glomerulus / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D050199:Podocytes / Q000166:cytology / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D000097642:GADD45 Proteins
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D056970:Co-Repressor Proteins; D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins; C484858:Wtip protein, mouse; C104328:dendrin