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Podocin Inactivation in Mature Kidneys Causes Focal Segmental Glomerulosclerosis and Nephrotic Syndrome

Géraldine Mollet^*,, Julien Ratelade^*,, Olivia Boyer^*,,, Andrea Onetti Muda^*,, Ludivine Morisset^*,, Tiphaine Aguirre Lavin^*,, David Kitzis^*,, Margaret J. Dallman^||, Laurence Bugeon^||, Norbert Hubner^¶, Marie-Claire Gubler^*,, Corinne Antignac^*,,** and Ernie L. Esquivel^*,

*INSERM, U574, Hôpital Necker-Enfants Malades, Paris, France;
Faculté de Médecine René Descartes, Université Paris Descartes, Paris, France;
Pediatric Nephrology Department and
**Department of Genetics, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France;
Department of Pathology, Campus Biomedico University, Rome, Italy;
^||Department of Biological Sciences, Imperial College London, London, England; and
^¶Max-Delbruck Center for Molecular Medicine, Berlin, Germany

Correspondence: Dr. Corinne Antignac, INSERM U574, 6ème étage, Tour Lavoisier, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75015 Paris, France. Phone: +33-1-4449-4552; Fax: +33-1-4449-0290; E-mail: corinne.antignac{at}inserm.fr

Received for publication April 8, 2009. Accepted for publication June 10, 2009.

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.

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J. Am. Soc. Nephrol. 2009 20: A12. [Full Text] [PDF]

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				M. R. Pollak Surprising Results following Conditional Podocyte Inactivation J. Am. Soc. Nephrol., October 1, 2009; 20(10): 2086 - 2088. [Full Text] [PDF]

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673