Focal and Segmental Glomerulosclerosis in Mice with Podocyte-Specific Expression of Mutant α-Actinin-4

Abstract

ABSTRACT. Mutations in the gene encoding α-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 α-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 humanACTN4-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-proteinuricACTN4-mutant mice. Immunofluorescence confirmed podocyte-specific expression of mutant α-actinin-4, and real-time RT-PCR revealed that HA-ACTN4mRNA levels were higher in proteinuricversusnon-proteinuricACTN4-mutant mice. Only proteinuric mice exhibited histologic features consistent with humanACTN4-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, proteinuricACTN4-mutant kidneys exhibited significantly reduced mRNA and protein levels of the slit diaphragm component, nephrin. This newly developed mouse model of humanACTN4-associated FSGS suggests a cause-and-effect relationship between actin cytoskeleton dysregulation by mutant α-actinin-4 and the deterioration of the nephrin-supported slit diaphragm complex. E-mail: ckennedy@uottawa.ca