Reactive Oxygen Species Promote Caspase-12 Expression and Tubular Apoptosis in Diabetic Nephropathy

被引:96
作者
Brezniceanu, Marie-Luise [1 ]
Lau, Cara J. [1 ]
Godin, Nicolas [1 ]
Chenier, Isabelle [1 ]
Duclos, Alain [1 ]
Ethier, Jean [1 ]
Filep, Janos G. [2 ]
Ingelfinger, Julie R. [3 ]
Zhang, Shao-Ling [1 ]
Chan, John S. D. [1 ]
机构
[1] Univ Montreal, CHU Montreal, Hotel Dieu Hosp, Ctr Rech, Montreal, PQ H2W 1T8, Canada
[2] Univ Montreal, Maisonneuve Rosemont Hosp, Ctr Rech, Montreal, PQ H2W 1T8, Canada
[3] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pediat Nephrol Unit, Boston, MA USA
来源
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY | 2010年 / 21卷 / 06期
基金
美国国家卫生研究院; 加拿大健康研究院;
关键词
ENDOPLASMIC-RETICULUM STRESS; ANGIOTENSINOGEN GENE-EXPRESSION; INTERSTITIAL FIBROSIS; CELL APOPTOSIS; ACTIVATION; GLUCOSE; DEATH; OVEREXPRESSION; CYTOTOXICITY; CATALASE;
D O I
10.1681/ASN.2009030242
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Apoptosis of tubular epithelial cells contributes to the tubular atrophy that accompanies diabetic nephropathy. Reactive oxygen species (ROS) promote tubular apoptosis, but the mechanisms by which this occurs are incompletely understood. Here, we sought proapoptotic genes that ROS differentially upregulate in renal proximal tubular cells of diabetic (db/db) mice. We performed microarray analysis using total RNA from freshly isolated renal proximal tubules of nondiabetic, diabetic, and diabetic transgenic mice overexpressing catalase in the proximal tubule (thereby attenuating ROS). We observed greater expression of caspase-12 in the proximal tubules of the diabetic mice compared with the nondiabetic and diabetic transgenic mice. Quantitative PCR and immunohistochemistry confirmed the enhanced expression of caspase-12, as well as members of the endoplasmic reticulum stress-induced apoptotic pathway. Ex vivo, albumin induced caspase-12 activity and expression (protein and mRNA) and mRNA expression of the CCAT/enhancer-binding protein homologous protein in freshly isolated wildtype proximal tubules but not in catalase-overexpressing proximal tubules. In vitro, albumin stimulated activity of both caspase-12 and caspase-3 as well as expression of caspase-12 and CCAT/enhancer-binding protein homologous protein in a human proximal tubule cell line (HK-2). The free radical scavenger tiron inhibited these effects. Furthermore, knockdown of caspase-12 with small interfering RNA reduced albumin-induced apoptosis in HK-2 cells. Taken together, these studies demonstrate that albuminuria may induce tubular apoptosis through generation of ROS and the subsequent expression and activation of endoplasmic reticulum stress genes in the diabetic kidney.
引用
收藏
页码:943 / 954
页数:12
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