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PMID: 14701729 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Early glomerular filtration defect and severe renal disease in podocin-deficient mice.

Molecular and cellular biology ·Vol. 24 ·No. 2 ·2004-01-00 ·Pages 550-60

Roselli S, Heidet L, Sich M, Henger A, Kretzler M, Gubler MC, Antignac C

Abstract

Podocytes are specialized epithelial cells covering the basement membrane of the glomerulus in the kidney. The molecular mechanisms underlying the role of podocytes in glomerular filtration are still largely unknown. We generated podocin-deficient (Nphs2-/-) mice to investigate the function of podocin, a protein expressed at the insertion of the slit diaphragm in podocytes and defective in a subset of patients with steroid-resistant nephrotic syndrome and focal and segmental glomerulosclerosis. Nphs2-/- mice developed proteinuria during the antenatal period and died a few days after birth from renal failure caused by massive mesangial sclerosis. Electron microscopy revealed the extensive fusion of podocyte foot processes and the lack of a slit diaphragm in the remaining foot process junctions. Using real-time PCR and immunolabeling, we showed that the expression of other slit diaphragm components was modified in Nphs2-/- kidneys: the expression of the nephrin gene was downregulated, whereas that of the ZO1 and CD2AP genes appeared to be upregulated. Interestingly, the progression of the renal disease, as well as the presence or absence of renal vascular lesions, depends on the genetic background. Our data demonstrate the crucial role of podocin in the establishment of the glomerular filtration barrier and provide a suitable model for mapping and identifying modifier genes involved in glomerular diseases caused by podocyte injuries.

MeSH Terms
Adherens Junctions/pathology Animals Animals, Newborn Base Sequence DNA/genetics Disease Models, Animal Female Glomerulosclerosis, Focal Segmental/genetics,pathology Humans Intracellular Signaling Peptides and Proteins Kidney Diseases/genetics,pathology,physiopathology Kidney Glomerulus/pathology,physiopathology Male Membrane Proteins/deficiency,genetics Mice Mice, Inbred C57BL Microscopy, Electron Proteinuria/genetics,physiopathology Renal Insufficiency/genetics,physiopathology
Chemicals
Intracellular Signaling Peptides and Proteins Membrane Proteins NPHS2 protein DNA
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Roselli Séverine
INSERM U574, Hôpital Necker-Enfants Malades, Université René Descartes, Tour Lavoisier 6ème étage, 75743 Paris, France.
Heidet Laurence
Sich Mireille
Henger Anna
Kretzler Matthias
Gubler Marie-Claire
Antignac Corinne
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.24.2.550-560.2004
Published
2004-01-00
Pages
550-60
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC343810
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.24.2.550-560.2004 PMC Full Text View journal details
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