title: Loss of the podocyte-expressed transcription factor Tcf21/Pod1 results in podocyte differentiation defects and FSGS.
abstract: Podocytes are terminally differentiated cells with an elaborate cytoskeleton and are critical components of the glomerular barrier. We identified a bHLH transcription factor, Tcf21, that is highly expressed in developing and mature podocytes. Because conventional Tcf21 knockout mice die in the perinatal period with major cardiopulmonary defects, we generated a conditional Tcf21 knockout mouse to explore the role of this transcription factor in podocytes in vivo. Tcf21 was deleted from podocytes and podocyte progenitors using podocin-cre (podTcf21) and wnt4-cre (wnt4creTcf21) driver strains, respectively. Loss of Tcf21 from capillary-loop stage podocytes (podTcf21) results in simplified glomeruli with a decreased number of endothelial and mesangial cells. By 5 weeks of age, 40% of podTcf21 mice develop massive proteinuria and lesions similar to FSGS. Notably, the remaining 60% of mice do not develop proteinuria even when aged to 8 months. By contrast, earlier deletion of Tcf21 from podocyte precursors (wnt4creTcf21) results in a profound developmental arrest of podocyte differentiation and renal failure in 100% of mice during the perinatal period. Taken together, our results demonstrate a critical role for Tcf21 in the differentiation and maintenance of podocytes. Identification of direct targets of this transcription factor may provide new therapeutic avenues for proteinuric renal disease, including FSGS.
authors.affiliation: The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, Chiba, Japan;
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Maezawa
authors.affiliation: The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Feinberg Cardiovascular Research Institute and Division of Nephrology and Hypertension, Northwestern University, Chicago, Illinois;
authors.forename: Tuncer
authors.initials: T
authors.lastname: Onay
authors.affiliation: The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada;
authors.forename: Rizaldy P
authors.initials: RP
authors.lastname: Scott
authors.affiliation: Academic Renal Unit, University of Bristol, Bristol, United Kingdom;
authors.forename: Lindsay S
authors.initials: LS
authors.lastname: Keir
authors.affiliation: The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada;
authors.forename: Henrik
authors.initials: H
authors.lastname: Dimke
authors.affiliation: The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Feinberg Cardiovascular Research Institute and Division of Nephrology and Hypertension, Northwestern University, Chicago, Illinois;
authors.forename: Chengjin
authors.initials: C
authors.lastname: Li
authors.affiliation: The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada;
authors.forename: Vera
authors.initials: V
authors.lastname: Eremina
authors.affiliation: Neuroscience and Mental Health Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada;
authors.forename: Yuko
authors.initials: Y
authors.lastname: Maezawa
authors.affiliation: The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden;
authors.forename: Marie
authors.initials: M
authors.lastname: Jeansson
authors.affiliation: Biocenter and Infotech Oulu, Laboratory of Developmental Biology, Faculty of Biochemisty and Molecular Medicine, Oulu Center for Cell Matrix Research, University of Oulu, Finland;
authors.forename: Jingdong
authors.initials: J
authors.lastname: Shan
authors.affiliation: Division of Respirology, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada;
authors.forename: Matthew
authors.initials: M
authors.lastname: Binnie
authors.affiliation: Department of Nephrology, RAMBAM Health Care Campus, Haifa, Israel; and.
authors.forename: Moshe
authors.initials: M
authors.lastname: Lewin
authors.affiliation: Feinberg Cardiovascular Research Institute and Division of Nephrology and Hypertension, Northwestern University, Chicago, Illinois;
authors.forename: Asish
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Renal Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Miner
authors.affiliation: Biocenter and Infotech Oulu, Laboratory of Developmental Biology, Faculty of Biochemisty and Molecular Medicine, Oulu Center for Cell Matrix Research, University of Oulu, Finland;
authors.forename: Seppo J
authors.initials: SJ
authors.lastname: Vainio
authors.affiliation: The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Feinberg Cardiovascular Research Institute and Division of Nephrology and Hypertension, Northwestern University, Chicago, Illinois; quaggin@northwestern.edu.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Quaggin
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D016922:Cellular Senescence / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D007678:Kidney Glomerulus / Q000196:embryology / Q000473:pathology / Q000503:physiopathology; D007763:Lac Operon; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D050199:Podocytes / Q000473:pathology / Q000502:physiology*; D011507:Proteinuria / Q000235:genetics / Q000473:pathology / Q000503:physiopathology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; C112923:Tcf21 protein, mouse
keywords: diabetic nephropathy; focal segmental glomerulosclerosis; podocyte; transcription factors