An inducible mouse model for PAX2-dependent glomerular disease: insights into a complex pathogenesis.
Pax2 is a transcription factor with important functions during kidney development . Ectopic expression of Pax2 in podocytes has been reported in various glomerular diseases , but the functional relevance remains unknown. We developed an inducible mouse model that allows activation of Pax2 specifically in podocytes. Persistent expression of Pax2 did not interfere with the initial differentiation of podocytes, but mice ectopically expressing PAX2 developed end-stage renal failure soon after birth. Similarly, activation of PAX2 in healthy adult animals resulted in renal disease within 3 weeks after podocyte-specific induction of a deleter Cre. PAX2 activation caused repression of the podocyte key regulator molecule Wt1 and consequently a dramatic reduction of nephrin expression. Recruitment of the groucho-related protein TLE4 may be involved in converting Pax2 into a transcriptional repressor of Wt1. Finally, treatment of mice with an angiotensin-converting enzyme (ACE) inhibitor normalized renal function and induced upregulation of the important structural molecule nephrin via a Wt1-independent pathway. Our data demonstrate the functional significance of PAX2 reexpression in mature podocytes for the development of glomerular diseases and suggest that reactivation of PAX genes in terminally differentiated cells leads to a more dedifferentiated phenotype.
Wagner
Kay-Dietrich
KD
INSERM U636, Nice, France.
Wagner
Nicole
N
Guo
Jian-Kan
JK
Elger
Marlies
M
Dallman
Margaret J
MJ
Bugeon
Laurence
L
Schedl
Andreas
A
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D004656:Enalapril / Q000627:therapeutic use; D005786:Gene Expression Regulation; D007676:Kidney Failure, Chronic / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D051762:PAX2 Transcription Factor / Q000235:genetics / Q000502:physiology*; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D011507:Proteinuria / Q000188:drug therapy; D025721:WT1 Proteins / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D008565:Membrane Proteins; D051762:PAX2 Transcription Factor; C497319:Pax2 protein, mouse; D025721:WT1 Proteins; C113267:nephrin; D004656:Enalapril