Blockage of the lysosome-dependent autophagic pathway contributes to complement membrane attack complex-induced podocyte injury in idiopathic membranous nephropathy

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 co...

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Published in:Scientific reports 2017-08, Vol.7 (1), p.8643-18, Article 8643
Main Authors: Liu, Wei Jing, Li, Zhi-hang, Chen, Xiao-cui, Zhao, Xiao-lu, Zhong, Zhen, Yang, Chen, Wu, Hong-luan, An, Ning, Li, Wei-yan, Liu, Hua-feng
Format: Article
Language:English
Subjects:
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Acidification
Apoptosis
Autophagy
Chloroquine
Enzymatic activity
Homeostasis
Humanities and Social Sciences
Lysosomes
Membrane attack complex
Membranous nephropathy
multidisciplinary
Nephropathy
Ovalbumin
Phagocytosis
Phagosomes
Science
Science (multidisciplinary)
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Summary: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 the BECN1 expression 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.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-017-07889-z