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Journal of Signal Transduction
Volume 2011 (2011), Article ID 563128, 11 pages
http://dx.doi.org/10.1155/2011/563128
Review Article

Podocyte Injury Associated with Mutant α-Actinin-4

1Department of Medicine, McGill University Health Centre, McGill University, Montreal, QC, Canada H3A 1A1
2Division of Nephrology, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, QC, Canada H3A 1A1
3Kidney Research Centre, Department of Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada K1H 8M5
4Departments of Medicine and CMM, Ottawa Hospital Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, ON, Canada K1H 8M5

Received 14 March 2011; Accepted 8 May 2011

Academic Editor: Céline M. DerMardirossian

Copyright © 2011 Andrey V. Cybulsky and Chris R. J. Kennedy. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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.