Abstract
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.
Highlights
During the past decade, there has been a remarkable rise in the frequency of idiopathic membranous nephropathy (IMN), which might predominate over IgA nephropathy to become the leading type of primary glomerulopathy in the near future in some developing countries, including China with a 13% annual increase[1]
We found that more light chain 3 (LC3)-positive vacuoles were accumulated in the podocytes of renal tissues from patients with IMN compared with those from controls (Fig. 1B)
To determine the main nodes of this process that participate in autophagy inactivation, we investigated the detailed mechanism in a sublytic C5b-9 membrane attack model in vitro, since the increased expression of p62 and LC3 was found to be C5b-9-dependent
Summary
There has been a remarkable rise in the frequency of idiopathic membranous nephropathy (IMN), which might predominate over IgA nephropathy to become the leading type of primary glomerulopathy in the near future in some developing countries, including China with a 13% annual increase[1]. The activity and action of autophagy were studied in a sublytic C5b-9 membrane attack model after exposure of podocytes to the zymosan-treated serum, since zymosan could promote rapid C3 cleavage through assembly and protection of the amplification convertase on its surface and produce sera enriched with soluble C5b-914–16.
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