Blockage of the lysosome-dependent autophagic pathway contributes to complement membrane attack complex-induced podocyte injury in idiopathic membranous nephropathy.
Blockage of the lysosome-dependent autophagic pathway contributes to complement membrane attack complex-induced podocyte injury in idiopathic membranous nephropathy.
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溶酶体依赖性自噬途径的阻断导致特发性膜性肾病中补体膜攻击复合物诱导的足细胞损伤
DOI：
10.1038/s41598-017-07889-z
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发表时间：
2017-08-17
影响因子：
4.6
通讯作者：
Liu HF
中科院分区：
文献类型：
--
作者：
Liu WJ;Li ZH;Chen XC;Zhao XL;Zhong Z;Yang C;Wu HL;An N;Li WY;Liu HF
自噬介导的足细胞稳态失调被认为在特发性膜性肾病（IMN）中发挥作用。在本研究中，自噬活性和溶酶体的变化进行了研究，足细胞的IMN患者和培养的足细胞暴露于sublytic末端补体复合物，C5 b-9。C5 b-9可上调患者足细胞和C5 b-9损伤足细胞模型中LC 3阳性斑点的数量和p62的表达。LC 3-II的溶酶体周转没有受到影响，尽管足细胞暴露于C5 b-9后BECN 1的表达水平上调。C5 b-9还引起自噬体数量的显著增加，但不引起自溶酶体数量的显著增加，表明C5 b-9损害自噬体的溶酶体降解。此外，C5 b-9加剧了足细胞的凋亡，这可以通过氯喹处理来模拟，表明C5 b-9至少部分地通过抑制自噬来触发足细胞损伤。随后的研究表明，C5 b-9触发溶酶体膜透化，这可能导致酶活性降低、溶酶体酸化缺陷和DQ-卵清蛋白降解抑制。综上所述，我们的研究结果表明，溶酶体依赖性自噬途径被C5 b-9阻断，这可能在IMN发展过程中的足细胞损伤中发挥关键作用。
Dysregulation of autophagy-mediated podocyte homeostasis is proposed to play a role in idiopathic membranous nephropathy (IMN). In the present study, autophagic activity and lysosomal alterations were investigated in podocytes of IMN patients and in cultured podocytes exposed to sublytic terminal complement complex, C5b-9. C5b-9 upregulated the number of LC3 positive puncta and the expression of p62 in patient podocytes and in C5b-9 injuried podocyte model. The lysosomal turnover of LC3-II was not influenced, although theBECN1expression level was upregulated after exposure of podocytes to C5b-9. C5b-9 also caused a significant increase in the number of autophagosomes but not autolysosomes, suggesting that C5b-9 impairs the lysosomal degration of autophagosomes. Moreover, C5b-9 exacerbated the apoptosis of podocytes, which could be mimicked by chloroquine treatment, indicating that C5b-9 triggered podocyte injury, at least partially through inhibiting autophagy. Subsequent studies revealed that C5b-9 triggered lysosomal membrane permeabilization, which likely caused the decrease in enzymatic activity, defective acidification of lysosomes, and suppression of DQ-ovalbumin degradation. Taken together, our results suggest that the lysosomal-dependent autophagic pathway is blocked by C5b-9, which may play a key role in podocyte injury during the development of IMN.
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DOI：
10.1083/jcb.139.1.193
发表时间：
1997-10-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Mundel P;Heid HW;Mundel TM;Krüger M;Reiser J;Kriz W
通讯作者：
Kriz W
影响因子：
13.3
作者：
Liu WJ;Luo MN;Tan J;Chen W;Huang LZ;Yang C;Pan Q;Li B;Liu HF
通讯作者：
Liu HF
影响因子：
3.7
作者：
Carson JM;Okamura K;Wakashin H;McFann K;Dobrinskikh E;Kopp JB;Blaine J
通讯作者：
Blaine J
影响因子：
15.9
作者：
Hartleben, Bjoern;Goedel, Markus;Huber, Tobias B.
通讯作者：
Huber, Tobias B.
影响因子：
13.2
作者：
Decuypere, Jean-Paul;Ceulemans, Laurens J.;Jochmans, Ina
通讯作者：
Jochmans, Ina