Podocyte Injury Associated with Mutant α-Actinin-4

الملخص EN

Focal segmental glomerulosclerosis (FSGS) is an important cause of proteinuria and nephrotic syndrome in humans.

The pathogenesis of FSGS may be associated with glomerular visceral epithelial cell (GEC; podocyte) injury, leading to apoptosis, detachment, and “podocytopenia”, followed by glomerulosclerosis.

Mutations in α-actinin-4 are associated with FSGS in humans.

In cultured GECs, α-actinin-4 mediates adhesion and cytoskeletal dynamics.

FSGS-associated α-actinin-4 mutants show increased binding to actin filaments, compared with the wild-type protein.

Expression of an α-actinin-4 mutant in mouse podocytes in vivo resulted in proteinuric FSGS.

GECs that express mutant α-actinin-4 show defective spreading and motility, and such abnormalities could alter the mechanical properties of the podocyte, contribute to cytoskeletal disruption, and lead to injury.

The potential for mutant α-actinin-4 to injure podocytes is also suggested by the characteristics of this mutant protein to form microaggregates, undergo ubiquitination, impair the ubiquitin-proteasome system, enhance endoplasmic reticulum stress, and exacerbate apoptosis.