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Interleukin-7 Is Associated with Clinical and Pathological Activities in Immunoglobulin A Nephropathy and Protects the Renal Proximal Tubule Epithelium from Cellular Fibrosis

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Abstract

Objective

Diagnosis of immunoglobulin A nephropathy (IgAN) requires the evaluation of renal biopsy specimens. However, renal biopsy is an invasive procedure and is not frequently performed for various reasons. Thus, recognized noninvasive biomarkers for predicting IgAN progression are urgently needed.

Methods

In the present study, we included 86 IgAN patients with renal biopsy from June 2015 to May 2016 and had their plasma interleukin-7 (IL-7) level measured with ELISA. The association between the plasma IL-7 level and clinico-pathological characteristics was analyzed. Immunohistochemical staining was used to assay the in situ expression of IL-7 in vivo. Western blotting was performed to examine the production of extracellular matrix, p-mTOR and the markers of autophagy under the treatment of IL-7 after TGF-β1 stimulation in renal tubular epithelial cells.

Results

IL-7 was significantly decreased in patients with IgAN compared to healthy subjects (2.3077 vs. 8.6294 pg/mL, P<0.0001). There was a significant difference in the plasma IL-7 level between tubular atrophy/interstitial fibrosis T0 and T2 classes (P=0.0064). A lower plasma IL-7 value in patients at the time of biopsy indicated a poor renal outcome. In addition, IL-7 was over-expressed in renal tubular epithelial cells and significantly attenuated transforming growth factor βl-induced extracellular matrix production by suppression of cellular autophagy via activation of mTOR1 signaling.

Conclusion

These results suggested that IL-7 might be a noninvasive biomarker for predicating IgAN. It protected renal proximal tubular epithelial cells from cellular fibrosis by inhibiting autophagy via mTORl signaling.

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References

  1. Wyatt RJ, Julian BA. IgA nephropathy. N Engl J Med, 2013,368(25):2402–2414

    Article  CAS  Google Scholar 

  2. Working Group of the International IgA Nephropathy Network and the Renal Pathology Society, Cattran DC, Coppo R, et al. The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification. Kidney Int, 2009,76(5):534–545

    Article  Google Scholar 

  3. van Roon JA, Verweij MC, Wijk MW, et al. Increased intraarticular interleukin-7 in rheumatoid arthritis patients stimulates cell contact-dependent activation of CD4(+) T cells and macrophages. Arthritis Rheum, 2005,52(6):1700–1710

    Article  CAS  Google Scholar 

  4. Harrison C. Autoimmune disease: Targeting IL-7 reverses type 1 diabetes. Nat Rev Drug Discov, 2012, 11(8):599

    Article  CAS  Google Scholar 

  5. Ben-David H, Sharabi A, Parameswaran R, et al. A tolerogenic peptide down-regulates mature B cells in bone marrow of lupus-afflicted mice by inhibition of interleukin-7, leading to apoptosis. Immunology, 2009, 128(2):245–252

    Article  CAS  Google Scholar 

  6. Lundström W, Fewkes NM, Mackall CL. IL-7 in human health and disease. Semin Immunol, 2012,24(3):218–224

    Article  Google Scholar 

  7. Zhai SB, Zhao LY, Zhang Y, et al. Interleukin-7 stimulation inhibits nephrin activation and induces podocyte injury. Biochem Biophys Res Commun, 2018, 507(1–4):100–105

    Article  CAS  Google Scholar 

  8. Penaranda C, Kuswanto W, Hofmann J, et al. IL-7 receptor blockade reverses autoimmune diabetes by promoting inhibition of effector/memory T cells. Proc Natl Acad Sci USA, 2012,109(31):12 668–12 673

    Article  CAS  Google Scholar 

  9. Venet F, Demaret J, Blaise BJ, et al. IL-7 Restores T lymphocyte immunometabolic failure in septic shock patients through mTOR activation. J Immunol, 2017,199(5):1606–1615

    Article  CAS  Google Scholar 

  10. Allgäuer A, Schreiner E, Ferrazzi F, et al. IL-7 Abrogates the immunosuppressive function of human double-negative T cells by activating Akt/mTOR signaling. J Immunol, 2015,195(7):3139–3148

    Article  Google Scholar 

  11. Aylett CH, Sauer E, Imseng S, et al. Architecture of human mTOR complex 1. Science, 2016,351(6268):48–52

    Article  CAS  Google Scholar 

  12. Dunlop EA, Tee AR. mTOR and autophagy: a dynamic relationship governed by nutrients and energy. Semin Cell Dev Biol, 2014,36:121–129

    Article  CAS  Google Scholar 

  13. Germain N, Viltart O, Loyens A, et al. Interleukin-7 plasma levels in human differentiate anorexia nervosa, constitutional thinness and healthy obesity. PloS One, 2016,11(9):e0161890

    Article  Google Scholar 

  14. De Benedetti F, Massa M, Pignatti P, et al. Elevated circulating interleukin-7 levels in patients with systemic juvenile rheumatoid arthritis. J Rheumatol, 1995,22(8): 1581–1585

    CAS  PubMed  Google Scholar 

  15. Neuhaus TJ, Shah V, Callard RE, et al. T-lymphocyte activation insteroid-sensitive nephrotic syndrome in childhood. Nephrol Dial Transplant, 1995,10(8):1348–1352

    CAS  PubMed  Google Scholar 

  16. Pellegrini M, Calzascia T, Elford AR, et al. Adjuvant IL-7 antagonizes multiple cellular and molecular inhibitory networks to enhance immunotherapies. Nat Med, 2009,15(5):528–536

    Article  CAS  Google Scholar 

  17. Zhang W, Du JY, Yu Q, et al. Interleukin-7 produced by intestinal epithelial cells in response to Citrobacter rodentium infection plays a major role in innate immunity against this pathogen. Infect Immun, 2015,83(8):3213–3223

    Article  CAS  Google Scholar 

  18. Higgins DF, Kimura K, Bernhardt WM, et al. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest, 2007,117(12):3810–3820

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Kawai T, Masaki T, Doi S, et al. PPAR-gamma agonist attenuates renal interstitial fibrosis and inflammation through reduction of TGF-beta. Lab Invest, 2009,89(1): 47–58

    Article  CAS  Google Scholar 

  20. Hsieh PF, Liu SF, Lee TC, et al. The role of IL-7 in renal proximal tubule epithelial cells fibrosis. Mol Immunol, 2012,50(1–2):74–82

    Article  CAS  Google Scholar 

  21. Huang M, Sharma S, Zhu L, et al. IL-7 inhibits fibroblast TGF-beta production and signaling in pulmonary fibrosis. J Clin Invest, 2002,109(7):931–937

    Article  CAS  Google Scholar 

  22. Jiang L, Xu L, Mao J, et al. Rheb/mTORC1 signaling promotes kidney fibroblast activation and fibrosis. J Am Soc Nephrol, 2013,24(7):1114–1126

    Article  CAS  Google Scholar 

  23. Lieberthal W, Levine JS. The role of the mammalian target of rapamycin (mTOR) in renal disease. J Am Soc Nephrol, 2009,20(12):2493–2502

    Article  CAS  Google Scholar 

  24. Novalic Z, van der Wal AM, Leonhard WN, et al. Dose-dependent effects of sirolimus on mTOR signaling and polycystic kidney disease. J Am Soc Nephrol, 2012, 23(5):842–853

    Article  CAS  Google Scholar 

  25. Wang S, Wilkes MC, Leof EB, et al. Noncanonical TGF-beta pathways, mTORC1 and Abl, in renal interstitial fibrogenesis. Am J Physiol Renal Physiol, 2010,298(1):F142–149

    Article  CAS  Google Scholar 

  26. Baisantry A, Bhayana S, Rong S, et al. Autophagy induces prosenescent changes in proximal tubular S3 segments. J Am Soc Nephrol, 2016,27(6):1609–1616

    Article  CAS  Google Scholar 

  27. Ding Y, Kim Sl, Lee SY, et al. Autophagy regulates TGF-beta expression and suppresses kidney fibrosis induced by unilateral ureteral obstruction. J Am Soc Nephrol, 2014,25(12):2835–2846

    Article  CAS  Google Scholar 

  28. Zhu J, Zhang W, Zhang L, et al. IL-7 suppresses macrophage autophagy and promotes liver pathology in Schistosoma japonicum-infected mice. J Cell Mol, 2018,22(7):3353–3363

    Article  CAS  Google Scholar 

Download references

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Author notes

  1. The authors contributed equally to this work.

Authors and Affiliations

  1. Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Yuan-jun Deng, Xue-** Lin, **ao-qing Li, **-fan Lu, Yang Cai, Le-le Liu, Guang-chang Pei & Min Han

Authors
  1. Yuan-jun Deng
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  2. Xue-** Lin
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  3. **ao-qing Li
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  4. **-fan Lu
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  5. Yang Cai
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  6. Le-le Liu
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  7. Guang-chang Pei
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  8. Min Han
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Corresponding author

Correspondence to Min Han.

Additional information

This project was supported by grants from Huazhong University of Science and Technology Research Funds for Self-dependent Innovation (No. 2017KFYXJJ101), and the National Natural Science Foundation of China (No. 81703058, No. 81970591, and No. 82000656).

Conflict of Interest Statement

The authors declare no conflict of interest.

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Deng, Yj., Lin, Xp., Li, Xq. et al. Interleukin-7 Is Associated with Clinical and Pathological Activities in Immunoglobulin A Nephropathy and Protects the Renal Proximal Tubule Epithelium from Cellular Fibrosis. CURR MED SCI 41, 880–887 (2021). https://doi.org/10.1007/s11596-021-2409-z

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  • DOI: https://doi.org/10.1007/s11596-021-2409-z

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