Podocin inactivation in mature kidneys causes focal segmental glomerulosclerosis and nephrotic syndrome.
Podocin is a critical component of the glomerular slit diaphragm, and genetic mutations lead to both familial and sporadic forms of steroid-resistant nephrotic syndrome. In mice, constitutive absence of podocin leads to rapidly progressive renal disease characterized by mesangiolysis and/or mesangial sclerosis and nephrotic syndrome. Using established Cre-loxP technology, we inactivated podocin in the adult mouse kidney in a podocyte-specific manner. Progressive loss of podocin in the glomerulus recapitulated albuminuria, hypercholesterolemia, hypertension, and renal failure seen in nephrotic syndrome in humans. Lesions of FSGS appeared after 4 wk, with subsequent development of diffuse glomerulosclerosis and tubulointerstitial damage. Interestingly, conditional inactivation of podocin at birth resulted in a gradient of glomerular lesions, including mesangial proliferation, demonstrating a developmental stage dependence of renal histologic patterns of injury. The development of significant albuminuria in this model occurred only after early and focal foot process effacement had progressed to diffuse involvement, with complete absence of podocin immunolabeling at the slit diaphragm. Finally, we identified novel potential mediators and perturbed molecular pathways, including cellular proliferation, in the course of progression of renal disease leading to glomerulosclerosis, using global gene expression profiling.
Mollet
Géraldine
G
INSERM, U574, Hôpital Necker-Enfants Malades, Paris, France.
Ratelade
Julien
J
Boyer
Olivia
O
Muda
Andrea Onetti
AO
Morisset
Ludivine
L
Lavin
Tiphaine Aguirre
TA
Kitzis
David
D
Dallman
Margaret J
MJ
Bugeon
Laurence
L
Hubner
Norbert
N
Gubler
Marie-Claire
MC
Antignac
Corinne
C
Esquivel
Ernie L
EL
D000818:Animals; D005260:Female; D020869:Gene Expression Profiling; D005923:Glomerulosclerosis, Focal Segmental / Q000209:etiology*; D019426:Integrases / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D007668:Kidney / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000378:metabolism; D007684:Kidney Tubules / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D009404:Nephrotic Syndrome / Q000209:etiology*; D050199:Podocytes / Q000648:ultrastructure
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; C045073:Cre recombinase; D019426:Integrases