Polycystic kidney disease in SBM transgenic mice: role of c-myc in disease induction and progression.
SBM mouse is a unique transgenic model of polycystic kidney disease (PKD) produced by dysregulation of c-myc in the kidneys. Our previous demonstration that c-myc is overexpressed in human autosomal polycystic kidney disease (ADPKD) prompted us to investigate the pathogenetic role of c-myc in the induction and progression of the cystogenic phenotype in our mouse model. In young SBM kidneys, c-myc was two- to threefold increased with persistent expression levels into adulthood, an age when c-myc is normally undetectable. In situ hybridization analysis of the c-myc transgene demonstrated intense signal specifically overlying glomerular and tubular epithelium of developing cysts in fetal and young kidneys. Increased expression of c-myc correlated with the initiation and progression of the PKD phenotype as evidenced by early tubular and glomerular cysts at E16.5. Cyst number and size increased with age, with co-development of glomerular and tubular epithelial hyperplasia. Consistently, the mean renal proliferative index was increased approximately 5- to 20-fold in noncystic and cystic tubules of newborn SBM animals compared with littermate controls. Similarly, in fetal and newborn kidneys the tubular apoptotic indices were increased approximately three- to ninefold over controls. Both proliferation and apoptotic rates in cystic tubules approached levels in developing tubules from the normal nephrogenic zone. We conclude that the pathogenesis of PKD hinges on a critical imbalance in c-myc regulation of the opposing processes of cell proliferation and apoptosis, recapitulating the cellular phenomena in developing fetal kidney.
Trudel
M
M
Institut de Recherches Cliniques de Montreal, Faculte de Medecine de l'Universite de Montreal, Quebec, Canada. trudelm@ircm.umontreal.ca
Barisoni
L
L
Lanoix
J
J
D'Agati
V
V
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002455:Cell Division; D018450:Disease Progression; D005333:Fetus / Q000033:anatomy & histology; D017403:In Situ Hybridization; D007668:Kidney / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D051379:Mice / Q000196:embryology; D008822:Mice, Transgenic / Q000235:genetics*; D007690:Polycystic Kidney Diseases / Q000196:embryology / Q000235:genetics* / Q000473:pathology; D016133:Polymerase Chain Reaction; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D014158:Transcription, Genetic
D016271:Proto-Oncogene Proteins c-myc