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Inflammation Research

, Volume 66, Issue 9, pp 793–802 | Cite as

Montelukast improves the changes of cytoskeletal and adaptor proteins of human podocytes by interleukin-13

  • Tae-Sun Ha
  • Ja Ae Nam
  • Su-Bin Seong
  • Moin A. Saleem
  • Se Jin Park
  • Jae Il Shin
Original Research Paper

Abstract

Objective and design

Interleukin-13 (IL-13) has recently been reported to be a potential cytokine in the pathogenesis of minimal-change nephrotic syndrome (MCNS). However, the mechanistic insights associated with podocyte dysfunction mediated by IL-13-induced changes in various slit diaphragm (SD) and cytoskeletal molecules have not yet been shown in cultured human podocytes in vitro.

Materials

Human conditionally immortalized podocytes were used.

Treatment

Podocytes were incubated with various concentrations of IL-13 during the indicated time periods (6, 12, and 24 h) and montelukast was administered with the dose of 0.1 μg.

Results

Treatment of IL-13 resulted in a progressive decrease in distinct processes or projections of the human podocytes and high dose of IL-13 increased podocyte permeability in vitro at 6 h. IL-13 had a substantial impact on the redistribution and rearrangement of zonula occludens (ZO)-1, synaptopodin, α-actinin, CD2-associated protein (CD2AP) in podocytes and disrupted the cytoskeletal connections in a concentration-dependent manner on confocal microscopy. IL-13 also down-modulated ZO-1, synaptopodin, α-actinin, CD2AP, and p130Cas at protein levels and upregulated β-catenin and B7-1 in podocytes. Furthermore, we demonstrated that down-modulated changes in various SD and cytoskeletal structures of human podocytes induced by IL-13 was significantly restored after treatment with montelukast with upregulation of B7-1.

Conclusion

Our results suggest that targeting IL-13 may be one of the important cytokines in the pathogenesis of MCNS and targeting IL-13 could be one of the potential therapeutic strategies in MCNS.

Keywords

Interleukin-13 Slit diaphragm Cytoskeletal molecules B7-1 Podocytes Leukotriene receptor antagonists 

Notes

Acknowledgements

The authors would like to thank Keum Hwa Lee for arranging references and proof reading.

Author contributions

T-SH, JAN, S-BS, MAS, SJP and JIS designed study, coordinated data acquisition, statistically analyzed and interpreted the data, drafted and revised the manuscript. All authors read and approved the final manuscript.

Compliance with ethical standards

Conflict of interest

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) and funded by the Ministry of Education, Science and Technology (2011-0013789, 2013R1A1A1012112 and 2015R1C1A1A01052984) to J.I. Shin and partly supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2013R1A1A4A03006207) to T.-S. Ha.

Supplementary material

11_2017_1058_MOESM1_ESM.doc (602 kb)
Supplementary material 1 (DOC 602 kb)

References

  1. 1.
    Eddy AA, Symons JM. Nephrotic syndrome in childhood. Lancet. 2003;362:629–39.CrossRefPubMedGoogle Scholar
  2. 2.
    Cheung W, Wei CL, Seah CC, Jordan SC, Yap HK. Atopy, serum IgE, and interleukin-13 in steroid-responsive nephrotic syndrome. Pediatr Nephrol. 2004;19:627–32.CrossRefPubMedGoogle Scholar
  3. 3.
    Yap HK, Cheung W, Murugasu B, Sim SK, Seah CC, Jordan SC. Th1 and Th2 cytokine mRNA profiles in childhood nephrotic syndrome: evidence for increased IL-13 mRNA expression in relapse. J Am Soc Nephrol. 1999;10:529–37.PubMedGoogle Scholar
  4. 4.
    Lai KW, Wei CL, Tan LK, Tan PH, Chiang GS, Lee CG, et al. Overexpression of interleukin-13 induces minimal-change-like nephropathy in rats. J Am Soc Nephrol. 2007;18:1476–85.CrossRefPubMedGoogle Scholar
  5. 5.
    Park SJ, Saleem MA, Nam JA, Ha TS, Shin JI. Effects of interleukin-13 and montelukast on the expression of zonula occludens-1 in human podocytes. Yonsei Med J. 2015;56:426–32.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Welsh GI, Saleem MA. The podocyte cytoskeleton–key to a functioning glomerulus in health and disease. Nat Rev Nephrol. 2011;8:14–21.CrossRefPubMedGoogle Scholar
  7. 7.
    Ha TS. Roles of adaptor proteins in podocyte biology. World J Nephrol. 2013;2:1–10.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Greka A, Mundel P. Cell biology and pathology of podocytes. Annu Rev Physiol. 2012;74:299–323.CrossRefPubMedGoogle Scholar
  9. 9.
    Reiser J, Kriz W, Kretzler M, Mundel P. The glomerular slit diaphragm is a modified adherens junction. J Am Soc Nephrol. 2000;11:1–8.PubMedGoogle Scholar
  10. 10.
    George B, Holzman LB. Signaling from the podocyte intercellular junction to the actin cytoskeleton. Semin Nephrol. 2012;32:307–18.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Faul C, Asanuma K, Yanagida-Asanuma E, Kim K, Mundel P. Actin up: regulation of podocyte structure and function by components of the actin cytoskeleton. Trends Cell Biol. 2007;17:428–37.CrossRefPubMedGoogle Scholar
  12. 12.
    Saleem MA, O’Hare MJ, Reiser J, Coward RJ, Inward CD, Farren T, et al. A conditionally immortalized human podocyte cell line demonstrating nephrin and podocin expression. J Am Soc Nephrol. 2002;13:630–8.PubMedGoogle Scholar
  13. 13.
    Ding WY, Saleem MA. Current concepts of the podocyte in nephrotic syndrome. Kidney Res Clin Pract. 2012;31:87–93.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Garin EH, Mu W, Arthur JM, Rivard CJ, Araya CE, Shimada M, et al. Urinary CD80 is elevated in minimal change disease but not in focal segmental glomerulosclerosis. Kidney Int. 2010;78:296–302.CrossRefPubMedGoogle Scholar
  15. 15.
    Garin EH, Diaz LN, Mu W, Wasserfall C, Araya C, Segal M, et al. Urinary CD80 excretion increases in idiopathic minimal-change disease. J Am Soc Nephrol. 2009;20:260–6.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Ishimoto T, Cara-Fuentes G, Wang H, Shimada M, Wasserfall CH, Winter WE, et al. Serum from minimal change patients in relapse increases CD80 expression in cultured podocytes. Pediatr Nephrol. 2013;28:1803–12.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Shalhoub RJ. Pathogenesis of lipoid nephrosis: a disorder of T-cell function. Lancet. 1974;2:556–60.CrossRefPubMedGoogle Scholar
  18. 18.
    SY Zhang, Audard V, Fan Q, Pawlak A, Lang P, Sahali D. Immunopathogenesis of idiopathic nephrotic syndrome. Contrib Nephrol. 2011;169:94–106.CrossRefGoogle Scholar
  19. 19.
    Gwinner W, Landmesser U, Brandes RP, Kubat B, Plasger J, Eberhard O, et al. Reactive oxygen species and antioxidant defense in puromycin aminonucleoside glomerulopathy. J Am Soc Nephrol. 1997;8:1722–31.PubMedGoogle Scholar
  20. 20.
    Ha TS, Park HY, Seong SB, Ahn HY. Puromycin aminonucleoside increases podocyte permeability by modulating ZO-1 in an oxidative stress-dependent manner. Exp Cell Res. 2016;340:139–49.CrossRefPubMedGoogle Scholar
  21. 21.
    Ha TS. High-glucose and advanced glycosylation end products increased podocyte permeability via PI3-K/Akt signaling. J Mol Med (Berl). 2010;88:391–400.CrossRefPubMedGoogle Scholar
  22. 22.
    Ha TS, Choi JY, Park HY, Lee JS. Ginseng total saponin improves podocyte hyperpermeability induced by high glucose and advanced glycosylation endproducts. J Korean Med Sci. 2011;26:1316–21.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Ha TS, Choi JY, Park HY, Nam JA, Seong SB. Ginseng total saponin modulates the changes of α-actinin-4 in podocytes induced by diabetic conditions. J Ginseng Res. 2014;38:233–8.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Ha TS, Hong EJ, Han GD. Diabetic conditions downregulate the expression of CD2AP in podocytes via PI3-K/Akt signalling. Diabetes Metab Res Rev. 2015;31:50–60.CrossRefPubMedGoogle Scholar
  25. 25.
    Ha TS, Choi JY, Park HY, Han GD. Changes of podocyte p130Cas in diabetic conditions. J Nephrol. 2013;26:870–6.CrossRefPubMedGoogle Scholar
  26. 26.
    Ha TS, Choi JY, Park HY. Puromycin aminonucleoside modulates p130Cas of podocytes. Korean J Pediatr. 2012;55:371–6.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Zhou L, Liu Y. Wnt/β-catenin signalling and podocyte dysfunction in proteinuric kidney disease. Nat Rev Nephrol. 2015;11:535–45.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Dai C, Stolz DB, Kiss LP, Monga SP, Holzman LB, Liu Y. Wnt/beta-catenin signaling promotes podocyte dysfunction and albuminuria. J Am Soc Nephrol. 2009;20:1997–2008.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    He W, Kang YS, Dai C, Liu Y. Blockade of Wnt/β-catenin signaling by paricalcitol ameliorates proteinuria and kidney injury. J Am Soc Nephrol. 2011;22:90–103.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Reiser J, von Gersdorff G, Loos M, Oh J, Asanuma K, Giardino L, et al. Induction of B7-1 in podocytes is associated with nephrotic syndrome. J Clin Invest. 2004;113:1390–7.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Fiorina P, Vergani A, Bassi R, Niewczas MA, Altintas MM, Pezzolesi MG, et al. Role of podocyte B7-1 in diabetic nephropathy. J Am Soc Nephrol. 2014;25:1415–29.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Baye E, Gallazzini M, Delville M, Legendre C, Terzi F, Canaud G. The costimulatory receptor B7-1 is not induced in injured podocytes. Kidney Int. 2016;90:1037–44.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Leonardi S, Marchese G, Marseglia GL, La Rosa M. Montelukast in allergic diseases beyond asthma. Allergy Asthma Proc. 2007;28:287–91.CrossRefPubMedGoogle Scholar
  34. 34.
    Wu AY, Chik SC, Chan AW, Li Z, Tsang KW, Li W. Anti-inflammatory effects of high-dose montelukast in an animal model of acute asthma. Clin Exp Allergy. 2003;33:359–66.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing 2017

Authors and Affiliations

  1. 1.Department of Pediatrics, College of MedicineChungbuk National UniversityCheongjuKorea
  2. 2.Department of PediatricsChungbuk National University HospitalCheongjuKorea
  3. 3.Children’s and Academic Renal Unit, Southmead HospitalUniversity of BristolBristolUK
  4. 4.Department of Pediatrics, Daewoo General HospitalAjou University School of MedicineGeojeKorea
  5. 5.Department of PediatricsYonsei University College of MedicineSeoulRepublic of Korea
  6. 6.Department of Pediatric NephrologySeverance Children’s HospitalSeoulKorea
  7. 7.Institute of Kidney Disease ResearchYonsei University College of MedicineSeoulKorea

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