Heme Oxygenase-1 Inhibits Renal Tubular Macroautophagy in Acute Kidney Injury

被引:138
作者
Bolisetty, Subhashini [1 ,2 ,3 ,4 ,5 ]
Traylor, Amie M. [1 ,2 ,3 ]
Kim, Junghyun [1 ,2 ,3 ]
Joseph, Reny [1 ,2 ,3 ]
Ricart, Karina [1 ,3 ,4 ]
Landar, Aimee [1 ,3 ,4 ]
Agarwal, Anupam [1 ,2 ,3 ,4 ,5 ]
机构
[1] Univ Alabama, Div Nephrol, Birmingham, AL 35294 USA
[2] Univ Alabama, Dept Med, Birmingham, AL 35294 USA
[3] Univ Alabama, Nephrol Res & Training Ctr, Birmingham, AL 35294 USA
[4] Univ Alabama, Ctr Free Rad Biol, Birmingham, AL 35294 USA
[5] Univ Alabama, Dept Cell Biol, Birmingham, AL 35294 USA
来源
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY | 2010年 / 21卷 / 10期
基金
美国国家卫生研究院;
关键词
AUTOPHAGIC CELL-DEATH; EPITHELIAL-CELLS; CISPLATIN NEPHROTOXICITY; ENDOPLASMIC-RETICULUM; ENDOTHELIAL-CELLS; INDUCED APOPTOSIS; PROTECTIVE ROLE; GENE ABLATION; ISCHEMIA/REPERFUSION; MECHANISMS;
D O I
10.1681/ASN.2010030238
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
Autophagy is a tightly regulated, programmed mechanism to eliminate damaged organelles and proteins from a cell to maintain homeostasis. Cisplatin, a chemotherapeutic agent, accumulates in the proximal tubules of the kidney and causes dose-dependent nephrotoxicity, which may involve autophagy. In the kidney, cisplatin induces the protective antioxidant heme oxygenase-1 (HO-1). In this study, we examined the relationship between autophagy and HO-1 during cisplatin-mediated acute kidney injury (AKI). In wild-type primary proximal tubule cells (PTC), we observed a time-dependent increase in autophagy after cisplatin. In HO-1 PTC, however, we observed significantly higher levels of basal autophagy, impaired progression of autophagy, and increased apoptosis after cisplatin. Restoring HO-1 expression in these cells reversed the autophagic response and inhibited apoptosis after treatment with cisplatin. In vivo, although both wild-type and HO-1 deficient mice exhibited autophagosomes in the proximal tubules of the kidney in response to cisplatin, HO-1 deficient mice had significantly more autophagosomes, even in saline-treated animals. In addition, ecdysone-induced overexpression of HO-1 in cells led to a delay in autophagy progression, generated significantly lower levels of reactive oxygen species, and protected against cisplatin cytotoxicity. These findings demonstrsate that HO-1 inhibits autophagy, suggesting that the heme oxygenase system may contain therapeutic targets for AKI.
引用
收藏
页码:1702 / 1712
页数:11
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