期刊
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
卷 20, 期 10, 页码 2181-2189出版社
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2009040379
关键词
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资金
- EuReGene Network [5085]
- GIS-Institut des Maladies Rares
- Agence Nationale de la Recherche
- Genzyme Renal Innovations Program
- National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases Ruth Kirchstein National Research Service Award [DK065409]
- Ministere de I'Enseignement Superieur et de la Recherche
- Fondation de la Recherche Medicale
- Biotechnology and Biological Sciences Research Council [BB/C519670/1] Funding Source: researchfish
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 cliff use 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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