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This Article Full Text Full Text (PDF) All Versions of this Article: 297/4/F987    most recent 00055.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (1) Google Scholar Articles by Cybulsky, A. V. Articles by Kennedy, C. R. J. PubMed PubMed Citation Articles by Cybulsky, A. V. Articles by Kennedy, C. R. J.

Glomerular epithelial cell injury associated with mutant -actinin-4

¹Department of Medicine, McGill University Health Centre, McGill University, Montreal, Quebec; and ; ²Kidney Research Centre, Department of Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada

Submitted February 2, 2009 ; accepted in final form July 28, 2009

Focal segmental glomerulosclerosis (FSGS) may be associated with glomerular epithelial cell (GEC; podocyte) apoptosis due to acquired injury or mutations in -actinin-4. This study addresses how FSGS-associated mutant -actinin-4 may induce GEC injury, focusing on endoplasmic reticulum (ER) stress and metabolism of mutant -actinin-4 via the ubiquitin-proteasome system. In a model of experimental FSGS induced by expression of an -actinin-4 K256E transgene in podocytes, we show induction of ER stress, including upregulation of ER chaperones (bip, grp94), phosphorylation of the eukaryotic translation initiation factor-2 subunit, and induction of the proapop totic gene C/EBP homologous protein-10 (CHOP). To address mechanisms of ER stress, we studied signaling in cultured GEC and COS cells expressing -actinin-4 K256E. Previously, we showed that expression of this -actinin-4 mutant in GEC increased apoptosis. In the present study, we show that -actinin-4 K256E upregulates grp94 and CHOP expression in COS cells and significantly exacerbates induction of bip and CHOP in GEC in the presence of tunicamycin. ER stress was associated with aggregation and ubiquitination of -actinin-4 K256E and impairment of the ubiquitin-proteasome system. In addition, -actinin-4 K256E exacerbated apoptosis in the context of mild proteasome inhibition. Thus -actinin-4 K256E triggers several metabolic abnormalities, which may lead to GEC injury and glomerulosclerosis.

apoptosis; endoplasmic reticulum stress; glomerulonephritis; transgenic mice; ubiquitin-proteasome system