title: Impairment of podocyte function by diphtheria toxin--a new reversible proteinuria model in mice.
abstract: Diphtheria toxin (DTx) receptor (DTR)-mediated conditional cell ablation in transgenic mice is a powerful tool to analyze cell function in vivo. Transgenic mice with cell-specific expression of the human DTR have been developed that allow conditional depletion of these cells in vivo through administration of the toxin. We have performed a careful analysis of mice after DTx injection and found an unexpected side effect. Treatment of wild-type C57BL/6 mice with DTx leads to a marked transient and completely reversible proteinuria, as a consequence of podocyte dysfunction that is morphologically characterized by foot process fusion and detachment from the glomerular basal membrane. In vitro analysis displayed that DTx-treated podocytes show diminished attachment to basal membrane proteins. Five to 9 days after DTx application the mice recover completely. Glomerular proteinuria is a hallmark of glomerular disease due to dysfunction of the filtration barrier. Rodents have been extensively used experimentally to better define the mechanisms of disease induction and progression. However, nongenetic mouse models of proteinuric glomerular damage are limited and display various shortcomings. We suggest DTx-induced transient kidney dysfunction as a new reversible model of experimental podocyte injury, which could be used as an additional approach to complement studies in human.
authors.affiliation: Department of Immunemodulation at the Dermatology, University Hospital Erlangen, Erlangen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Goldwich
authors.forename: Alexander
authors.initials: A
authors.lastname: Steinkasserer
authors.forename: André
authors.initials: A
authors.lastname: Gessner
authors.forename: Kerstin
authors.initials: K
authors.lastname: Amann
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004167:Diphtheria Toxin / Q000633:toxicity*; D004195:Disease Models, Animal; D005260:Female; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D050199:Podocytes / Q000187:drug effects* / Q000502:physiology; D011507:Proteinuria / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology
chemical_list: D004167:Diphtheria Toxin; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; C113267:nephrin