Transgenic mice expressing nitroreductase gene under the control of the podocin promoter: a new murine model of inductible glomerular injury.
The present work identifies a new mouse model of inductible acute glomerular injury leading to focal segmental glomerulonephritis. We take advantage of the suicide gene/prodrug nitroreductase/CB1954 combination, in which nitroreductase converts CB1954, a monofunctional alkylating agent, into its toxic form. We generate two lines of transgenic mice in which the nitroreductase gene was placed under the control of the podocyte-specific gene podocin. The functional analysis of transgenic mice lines showed that CB1954 treatment induced a severe but transitory proteinuria. Sequential histopathological analysis was performed on serial kidney biopsies. Injured glomeruli showed acute lesions with early podocyte vacuolization and detachment, podocyte apoptosis, and cellular proliferation leading to a marked hypercellularity of the urinary space that was associated with collapsing of the glomerular tuft. After 1 month, progressive scarring lead to focal segmental glomerulosclerosis with fibrous capsular adhesion, hyalinosis, and podocytosis associated with interstitial fibrosis. The phenotype of podocytes was changed exhibiting dedifferentiation characterized by the loss of podocyte specific proteins/transcription factor and the expression of injury markers. Bowman's capsule cells were also involved in the cellular changes in a manner suggesting epithelial to mesenchymal transition. This model of podocyte injury in transgenic mice provides new insights into the cellular mechanisms of podocytopathies and their progression to scarring.
Macary
Guillaume
G
INSERM UMRS 872, Centre de recherche des Cordeliers, Equipe 3, 75006, Paris, France.
Rossert
Jérome
J
Bruneval
Patrick
P
Mandet
Chantal
C
Bélair
Marie-France
MF
Houillier
Pascal
P
Duong Van Huyen
Jean-Paul
JP
D000818:Animals; D001388:Aziridines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007678:Kidney Glomerulus / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009601:Nitroreductases / Q000235:genetics*; D050199:Podocytes / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000502:physiology
D001388:Aziridines; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; C100099:tretazicar; D009601:Nitroreductases