title: Podocin inactivation in mature kidneys causes focal segmental glomerulosclerosis and nephrotic syndrome.
abstract: 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.
authors.affiliation: INSERM, U574, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Mollet
authors.forename: Julien
authors.initials: J
authors.lastname: Ratelade
authors.forename: Olivia
authors.initials: O
authors.lastname: Boyer
authors.forename: Andrea Onetti
authors.initials: AO
authors.lastname: Muda
authors.forename: Ludivine
authors.initials: L
authors.lastname: Morisset
authors.forename: Tiphaine Aguirre
authors.initials: TA
authors.lastname: Lavin
authors.forename: David
authors.initials: D
authors.lastname: Kitzis
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Dallman
authors.forename: Laurence
authors.initials: L
authors.lastname: Bugeon
authors.forename: Norbert
authors.initials: N
authors.lastname: Hubner
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Gubler
authors.forename: Corinne
authors.initials: C
authors.lastname: Antignac
authors.forename: Ernie L
authors.initials: EL
authors.lastname: Esquivel
mesh_terms: 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
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; C045073:Cre recombinase; D019426:Integrases