Details

Autor(en) / Beteiligte

• Michaud, J.-L.R.
• Chaisson, K.M.
• Parks, R.J.
• Kennedy, C.R.J.

Titel

FSGS-associated α-actinin-4 (K256E) impairs cytoskeletal dynamics in podocytes

Ist Teil von

• Kidney international, 2006-09, Vol.70 (6), p.1054-1061

Ort / Verlag

New York, NY: Elsevier Inc

Erscheinungsjahr

2006

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Mutations in the ACTN4 gene, encoding the actin crosslinking protein α-actinin-4, are associated with a familial form of focal segmental glomerulosclerosis (FSGS). Mice with podocyte-specific expression of K256E α-actinin-4 develop foot process effacement and glomerulosclerosis, highlighting the importance of the cytoskeleton in podocyte structure and function. K256E α-actinin-4 exhibits increased affinity for F-actin. However, the downstream effects of this aberrant binding on podocyte dynamics remain unclear. Wild-type and K256E α-actinin-4 were expressed in cultured podocytes via adenoviral infection to determine the effect of the mutation on α-actinin-4 subcellular localization and on cytoskeletal-dependent processes such as adhesion, spreading, migration, and formation of foot process-like peripheral projections. Wild-type α-actinin-4 was detected primarily in the Triton-soluble fraction of podocyte lysates and localized to membrane-associated cortical actin and focal adhesions, with some expression along stress fibers. Conversely, K256E α-actinin-4 was detected predominantly in the Triton-insoluble fraction, was excluded from cortical actin, and localized almost exclusively along stress fibers. Both wild-type and K256E α-actinin-4-expressing podocytes adhered equally to an extracellular matrix (collagen-I). However, podocytes expressing K256E α-actinin-4 showed a reduced ability to spread and migrate on collagen-I. Lastly, K256E α-actinin-4 expression reduced the mean number of actin-rich peripheral projections. Our data suggest that aberrant sequestering of K256E α-actinin-4 impairs podocyte spreading, motility, and reduces the number of peripheral projections. Such intrinsic cytoskeletal derangements may underlie initial podocyte damage and foot process effacement encountered in ACTN4-associated FSGS.