title: Focal and segmental glomerulosclerosis in mice with podocyte-specific expression of mutant alpha-actinin-4.
abstract: Mutations in the gene encoding alpha-actinin-4 (ACTN4), an actin crosslinking protein, are associated with a form of autosomal dominant focal segmental glomerulosclerosis (FSGS). To better study its progression, a transgenic mouse model was developed by expressing murine alpha-actinin-4 containing a mutation analogous to that affecting a human FSGS family in a podocyte-specific manner using the murine nephrin promoter. Consistent with human ACTN4-associated FSGS, which shows incomplete penetrance, a proportion of the transgenic mice exhibited significant albuminuria (8 of 18), while the overall average systolic BP was elevated in both proteinuric and non-proteinuric ACTN4-mutant mice. Immunofluorescence confirmed podocyte-specific expression of mutant alpha-actinin-4, and real-time RT-PCR revealed that HA-ACTN4 mRNA levels were higher in proteinuric versus non-proteinuric ACTN4-mutant mice. Only proteinuric mice exhibited histologic features consistent with human ACTN4-associated FSGS, including segmental sclerosis and tuft adhesion of some glomeruli, tubular dilatation, mesangial matrix expansion, as well as regions of podocyte vacuolization and foot process fusion. Consistent with such podocyte damage, proteinuric ACTN4-mutant kidneys exhibited significantly reduced mRNA and protein levels of the slit diaphragm component, nephrin. This newly developed mouse model of human ACTN4-associated FSGS suggests a cause-and-effect relationship between actin cytoskeleton dysregulation by mutant alpha-actinin-4 and the deterioration of the nephrin-supported slit diaphragm complex.
authors.affiliation: Kidney Research Centre, Division of Nephrology, Department of Medicine, The Ottawa Hospital, Ottawa Health Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Michaud
authors.forename: Lyne I
authors.initials: LI
authors.lastname: Lemieux
authors.forename: Manon
authors.initials: M
authors.lastname: Dubé
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Vanderhyden
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Robertson
authors.forename: Chris R J
authors.initials: CR
authors.lastname: Kennedy
mesh_terms: D008841:Actin Cytoskeleton / Q000502:physiology; D000185:Actinin / Q000235:genetics* / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure; D019556:COS Cells; D003001:Cloning, Molecular; D018076:DNA, Complementary; D004195:Disease Models, Animal; D015870:Gene Expression; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D066298:In Vitro Techniques; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D016296:Mutagenesis; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011507:Proteinuria / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D019076:Transgenes / Q000502:physiology
chemical_list: C111453:ACTN4 protein, human; D000199:Actins; C491752:Actn4 protein, mouse; D018076:DNA, Complementary; D008565:Membrane Proteins; D008840:Microfilament Proteins; D011506:Proteins; C113267:nephrin; D000185:Actinin