Article Text

PDF
Increased autophagy is cytoprotective against podocyte injury induced by antibody and interferon-α in lupus nephritis
  1. Yuan-yuan Qi1,
  2. Xu-jie Zhou1,
  3. Fa-juan Cheng1,
  4. Ping Hou1,
  5. Ya-li Ren2,
  6. Su-xia Wang2,
  7. Ming-hui Zhao1,
  8. Li Yang1,
  9. Jennifer Martinez3,
  10. Hong Zhang1
  1. 1 Renal Division, Peking University First Hospital; Peking University Institute of Nephrology; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
  2. 2 Laboratory of Electron Microscopy, Ultrastructural Pathology Center, Peking University First Hospital, Beijing, China
  3. 3 Immunity, Inflammation, and Disease Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, Carolina, USA
  1. Correspondence to Dr Xu-jie Zhou, Renal Division, Peking University First Hospital; Peking University Institute of Nephrology; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing 100034, China; zhouxujie{at}bjmu.edu.cn

Abstract

Objective More recent studies suggested that defects in autophagy contribute to the pathogenesis of SLE, especially in adaptive immunity. Occurrence and progression of lupus nephritis (LN) is the end result of complex interactions between regulation of immune responses and pathological process by renal resident cells, but there is still a lot of missing information for an establishment on the role of autophagy in pathogenesis of LN and as a therapy target.

Methods Systemic and organ-specific aetiologies of autophagy were first evaluated by autophagy protein quantification in tissue homogenates in MRL lpr/lpr lupus prone and female C57BL mice. Analysis of gene expression was also adopted in human blood and urine sediments. Then, some key mediators of the disease, including complement inactivated serum, IgG from patients with LN (IgG-LN) and interferon (IFN)-α were chosen to induce podocyte autophagy. Podocyte injuries including apoptosis, podocin derangement, albumin filtration and wound healing were monitored simultaneously with autophagy steady-state and flux.

Results Elevated LC3B in kidney homogenates and increased autophagosomes in podocyte from MRL lpr/lpr were observed. In humans, mRNA levels of some key autophagy genes were increased in blood and urinary sediments, and podocyte autophagosomes were observed in renal biopsies from patients with LN. Complement inactivated serum, IgG-LN and IFN-α could induce podocyte autophagy in a time-dependent and dosage-dependent manner, and by reactive oxygen species production and mTORC1 inhibition, respectively. Autophagy inhibition aggravated podocyte damage whereas its inducer relieved the injury.

Conclusion Podocyte autophagy is activated in lupus-prone mice and patients with lupus nephritis. Increased autophagy is cytoprotective against antibody and interferon-α induced podocyte injury.

  • autophagy
  • lupus nephritis
  • podocyte
  • mTOR
  • rapamycin

Statistics from Altmetric.com

Footnotes

  • Handling editor Josef S Smolen

  • Contributors X-JZ ang HZ conceived the idea. Y-YQ, X-JZ, F-JC, PH, Y-LR and S-XW conducted the assays and were involved in the acquisition and analysis of data. Y-YQ, X-JZ, F-JC, LY, JM and HZ wrote the manuscript. Y-YQ, X-JZ, M-HZ, LY, JM and HZ revised the manuscript critically for important intellectual content. X-JZ supervised the research group and has given the final approval of the version to be published.

  • Funding This work was supported by grants from the National Science Foundation of China (no. 81570629), National Key Research and Development Program of China (2016YFC0904102), the Training Program of the Major Research Plan of the National Natural Science Foundation of China (91642120), Beijing Nova Program (Z171100001117023), Beijing Youth Top-notch Talent Support Program (2017000021223ZK31), Natural Science Foundation for Innovation Research Group of China (81621092), Beijing Natural Science Foundation (7152148), the University of Michigan Health System–Peking University Health Science Center Joint Institute for Translational and Clinical Research (BMU2017JI007), and Chinese Society of Nephrology (15020030591).

  • Disclaimer The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Institutional Review Board of the Peking University First Hospital.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement No additional unpublished data are available.

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.