Glomerular epithelial cell injury associated with mutant α-actinin-4

被引:35
作者
Cybulsky, Andrey V. [1 ]
Takano, Tomoko [1 ]
Papillon, Joan [1 ]
Bijian, Krikor [1 ]
Guillemette, Julie [1 ]
Kennedy, Chris R. J. [2 ]
机构
[1] McGill Univ, Dept Med, Ctr Hlth, Montreal, PQ, Canada
[2] Univ Ottawa, Dept Med, Kidney Res Ctr, Ottawa Hosp, Ottawa, ON, Canada
基金
加拿大健康研究院;
关键词
apoptosis; endoplasmic reticulum stress; glomerulonephritis; transgenic mice; ubiquitin-proteasome system; ENDOPLASMIC-RETICULUM STRESS; UNFOLDED PROTEIN RESPONSE; SEGMENTAL GLOMERULOSCLEROSIS; MOLECULAR CHAPERONES; PODOCYTE DEPLETION; ER STRESS; DISEASE; EXPRESSION; MICE; PROLIFERATION;
D O I
10.1152/ajprenal.00055.2009
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
Cybulsky AV, Takano T, Papillon J, Bijian K, Guillemette J, Kennedy CR. Glomerular epithelial cell injury associated with mutant alpha-actinin-4. Am J Physiol Renal Physiol 297: F987-F995, 2009. First published July 29, 2009; doi: 10.1152/ajprenal. 00055.2009.Focal segmental glomerulosclerosis (FSGS) may be associated with glomerular epithelial cell (GEC; podocyte) apoptosis due to acquired injury or mutations in alpha-actinin-4. This study addresses how FSGS-associated mutant alpha-actinin-4 may induce GEC injury, focusing on endoplasmic reticulum (ER) stress and metabolism of mutant alpha-actinin- 4 via the ubiquitin-proteasome system. In a model of experimental FSGS induced by expression of an alpha-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 alpha subunit, and induction of the proapoptotic gene C/EBP homologous protein-10 (CHOP). To address mechanisms of ER stress, we studied signaling in cultured GEC and COS cells expressing alpha-actinin-4 K256E. Previously, we showed that expression of this alpha-actinin-4 mutant in GEC increased apoptosis. In the present study, we show that alpha-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 alpha-actinin-4 K256E and impairment of the ubiquitin-proteasome system. In addition, alpha-actinin-4 K256E exacerbated apoptosis in the context of mild proteasome inhibition. Thus alpha-actinin-4 K256E triggers several metabolic abnormalities, which may lead to GEC injury and glomerulosclerosis.
引用
收藏
页码:F987 / F995
页数:9
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