Toll-like Receptor 9 Can be Activated by Endogenous Mitochondrial DNA to Induce Podocyte Apoptosis

被引：102

作者：

Bao, Wenduona ^{[1
]}

Xia, Hong ^{[1
]}

Liang, Yaojun ^{[1
]}

Ye, Yuting ^{[1
]}

Lu, Yuqiu ^{[1
]}

Xu, Xiaodong ^{[1
]}

Duan, Aiping ^{[1
]}

He, Jing ^{[1
]}

Chen, Zhaohong ^{[1
]}

Wu, Yan ^{[1
]}

Wang, Xia ^{[1
]}

Zheng, Chunxia ^{[1
]}

Liu, Zhihong ^{[1
]}

Shi, Shaolin ^{[1
]}

机构：

[1] Nanjing Univ, Sch Med, Jinling Hosp, Natl Clin Res Ctr Kidney Dis, Nanjing 210008, Jiangsu, Peoples R China

来源：

SCIENTIFIC REPORTS | 2016年 / 6卷

基金：

中国国家自然科学基金;

关键词：

PUROMYCIN AMINONUCLEOSIDE; PROTECTS PODOCYTES; LUPUS NEPHRITIS; OXIDANT STRESS; GROWTH-FACTOR; INJURY; EXPRESSION; DAMAGE; GLOMERULOSCLEROSIS; AUTOPHAGY;

D O I：

10.1038/srep22579

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Toll-like receptor 9 (TLR9) senses bacterial DNA characteristic of unmethylated CpG motifs to induce innate immune response. TLR9 is de novo expressed in podocytes of some patients with glomerular diseases, but its role in podocyte injury remains undetermined. Since TLR9 activates p38 MAPK and NFkB that are known to mediate podocyte apoptosis, we hypothesized thatTLR9 induces podocyte apoptosis in glomerular diseases. We treated immortalized podocytes with puromycin aminonucleosides (PAN) and observed podocyte apoptosis, accompanied by TLR9 upregulation. Prevention ofTLR9 upregulation by siRNA significantly attenuated NF KB p65 or p38 activity and apoptosis, demonstrating thatTLR9 mediates podocyte apoptosis. We next showed that endogenous mitochondrial DNA (mtDNA), whose CpG motifs are also unmethylated, is the ligand for TLR9, because PAN induced mtDNA accumulation in endolysosomes where TLR9 is localized, overexpression of endolysosomal DNase 2 attenuated PAN-induced p38 or p65 activity and podocyte apoptosis, and DNase 2 silencing was sufficient to activate p38 or p65 and induce apoptosis. In PAN-treated rats, TLR9 was upregulated in the podocytes, accompanied by increase of apoptosis markers. Thus, de novo expressed TLR9 may utilize endogenous mtDNA as the ligand to facilitate podocyte apoptosis, a novel mechanism underlying podocyte injury in glomerular diseases.

引用

页数：11

共 33 条

[1]

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