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Podocyte proteins in congenital and minimal change nephrotic syndrome

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Abstract

Background

Podocyte foot process effacement is a uniform finding in kidneys with heavy proteinuria. Its molecular mechanisms, however, are unsolved. We analyzed the expression of podocyte proteins in two kidney disorders: Congenital nephrotic syndrome of the Finnish type (CNF) and minimal change nephrotic syndrome (MCNS).

Methods

Immunoperoxidase and immunofluorescence stainings were used to semiquantitatively analyze the expression of 13 and 4 podocyte proteins from different cellular compartments in CNF and MCNS, respectively.

Results

The expression of a major slit diaphragm (SD) protein, Neph 1, showed a 46-fold decrease (p < 0.0001) in CNF kidneys as compared to controls. The three cytosolic adaptor proteins, podocin, NCK1/2, CD2AP, connecting SD proteins to the actin cytoskeleton were slightly upregulated (1.1-fold, 1.4-fold, and 3.3-fold, respectively). Also, the staining of the two actin-regulator proteins, ACTN4 and INF2, was modestly increased (2.2-fold and 1.7-fold, respectively, p < 0.0001). Staining for α3-integrin showed 1.9-fold increase (p < 0.0001) indicating that the major podocyte anchoring complex, α3β1, was well preserved in CNF glomeruli. In contrast to CNF kidneys, Neph1 FAT1, ACTN4, and CD2AP were quite normally expressed in proteinuric and non-proteinuric MCNS kidneys.

Conclusion

CNF kidneys lacking nephrin show decreased expression of other SD proteins but not cytosolic podocyte proteins involved in the foot process architecture or function. In MCNS kidneys, these changes in expression were not observed.

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References

  1. Shankland SJ. The podocyte’s response to injury: role in proteinuria and glomerulosclerosis. Kidney Int. 2006;69(12):2131–47.

    Article  CAS  PubMed  Google Scholar 

  2. Jalanko H. Congenital nephrotic syndrome. Pediatr Nephrol. 2009;24(11):2121–8.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Benoit G, Machuca E, Heidet L, Antignac C. Hereditary kidney diseases: highlighting the importance of classical Mendelian phenotypes. Ann NY Acad Sci. 2010;1214:83–98.

    Article  CAS  PubMed  Google Scholar 

  4. McCarthy HJ, Saleem MA. Genetics in clinical practice: nephrotic and proteinuric syndromes. Nephron Exp Nephrol. 2011;118(1):e1–8.

    Article  PubMed  Google Scholar 

  5. Kestilä M, Lenkkeri U, Männikkö M, Lamerdin J, McCready P, Putaala H, Ruotsalainen V, Morita T, Nissinen M, Herva R, Kashtan CE, Peltonen L, Holmberg C, Olsen A, Tryggvason K. Positionally cloned gene for a novel glomerular protein–nephrin—is mutated in congenital nephrotic syndrome. Mol Cell. 1998;1(4):575–82.

    Article  PubMed  Google Scholar 

  6. Patrakka J, Lahdenkari AT, Koskimies O, Holmberg C, Wartiovaara J, Jalanko H. The number of podocyte slit diaphragms is decreased in minimal change nephrotic syndrome. Pediatr Res. 2002;52(3):349–55.

    Article  PubMed  Google Scholar 

  7. Liu G, Kaw B, Kurfis J, Rahmanuddin S, Kanwar YS, Chugh SS. Neph1 and nephrin interaction in the slit diaphragm is an important determinant of glomerular permeability. J Clin Invest. 2003;112(2):209–21.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Heikkilä E, Ristola M, Havana M, Jones N, Holthöfer H, Lehtonen S. Trans-interaction of nephrin and Neph1/Neph3 induces cell adhesion that associates with decreased tyrosine phosphorylation of nephrin. Biochem J. 2011;435(3):619–28.

    Article  PubMed  Google Scholar 

  9. Inoue T, Yaoita E, Kurihara H, Shimizu F, Sakai T, Kobayashi T, Ohshiro K, Kawachi H, Okada H, Suzuki H, Kihara I, Yamamoto T. FAT is a component of glomerular slit diaphragms. Kidney Int. 2001;59(3):1003–12.

    Article  CAS  PubMed  Google Scholar 

  10. Schwarz K, Simons M, Reiser J, Saleem MA, Faul C, Kriz W, Shaw AS, Holzman LB, Mundel P. Podocin, a raft-associated component of the glomerular slit diaphragm, interacts with CD2AP and nephrin. J Clin Invest. 2001;108(11):1621–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Huber TB, Kottgen M, Schilling B, Walz G, Benzing T. Interaction with podocin facilitates nephrin signaling. J Biol Chem. 2001;276(45):41543–6.

    Article  CAS  PubMed  Google Scholar 

  12. Huber TB, Simons M, Hartleben B, Sernetz L, Schmidts M, Gundlach E, Saleem MA, Walz G, Benzing T. Molecular basis of the functional podocin-nephrin complex: mutations in the NPHS2 gene disrupt nephrin targeting to lipid raft microdomains. Hum Mol Genet. 2003;12(24):3397–405.

    Article  CAS  PubMed  Google Scholar 

  13. Jones N, New LA, Fortino MA, Eremina V, Ruston J, Blasutig IM, Aoudjit L, Zou Y, Liu X, Yu GL, Takano T, Quaggin SE, Pawson T. Nck proteins maintain the adult glomerular filtration barrier. J Am Soc Nephrol. 2009;20(7):1533–43.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Shih NY, Li J, Cotran R, Mundel P, Miner JH, Shaw AS. CD2AP localizes to the slit diaphragm and binds to nephrin via a novel C-terminal domain. Am J Pathol. 2001;159(6):2303–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Lynch DK, Winata SC, Lyons RJ, Hughes WE, Lehrbach GM, Wasinger V, Corthals G, Cordwell S, Daly RJ. A Cortactin-CD2-associated protein (CD2AP) complex provides a novel link between epidermal growth factor receptor endocytosis and the actin cytoskeleton. J Biol Chem. 2003;278(24):21805–13.

    Article  CAS  PubMed  Google Scholar 

  16. Kovacs EM, Verma S, Ali RG, Ratheesh A, Hamilton NA, Akhmanova A, Yap AS. N-WASP regulates the epithelial junctional actin cytoskeleton through a non-canonical post-nucleation pathway. Nat Cell Biol. 2011;13(8):934–43.

    Article  CAS  PubMed  Google Scholar 

  17. Dandapani SV, Sugimoto H, Matthews BD, Kolb RJ, Sinha S, Gerszten RE, Zhou J, Ingber DE, Kalluri R, Pollak MR. Alpha-actinin-4 is required for normal podocyte adhesion. J Biol Chem. 2007;282(1):467–77.

    Article  CAS  PubMed  Google Scholar 

  18. Kretzler M. Regulation of adhesive interaction between podocytes and glomerular basement membrane. Microsc Res Tech. 2002;57(4):247–53.

    Article  CAS  PubMed  Google Scholar 

  19. 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(9):428–37.

    Article  CAS  PubMed  Google Scholar 

  20. Patrakka J, Kestilä M, Wartiovaara J, Ruotsalainen V, Tissari P, Lenkkeri U, Männikkö M, Visapää I, Holmberg C, Rapola J, Tryggvason K, Jalanko H. Congenital nephrotic syndrome (NPHS1): features resulting from different mutations in Finnish patients. Kidney Int. 2000;58(3):972–80.

    Article  CAS  PubMed  Google Scholar 

  21. Patrakka J, Ruotsalainen V, Ketola I, Holmberg C, Heikinheimo M, Tryggvason K, Jalanko H. Expression of nephrin in pediatric kidney diseases. J Am Soc Nephrol. 2001;12(2):289–96.

    CAS  PubMed  Google Scholar 

  22. Kuusniemi AM, Merenmies J, Lahdenkari AT, Holmberg C, Salmela K, Karikoski R, Rapola J, Jalanko H. Glomerular sclerosis in kidneys with congenital nephrotic syndrome (NPHS1). Kidney Int. 2006;70(8):1423–31.

    Article  CAS  PubMed  Google Scholar 

  23. Lahdenkari AT, Lounatmaa K, Patrakka J, Holmberg C, Wartiovaara J, Kestilä M, Koskimies O, Jalanko H. Podocytes are firmly attached to glomerular basement membrane in kidneys with heavy proteinuria. J Am Soc Nephrol. 2004;15(10):2611–8.

    Article  PubMed  Google Scholar 

  24. Garg P, Verma R, Nihalani D, Johnstone DB, Holzman LB. Neph1 cooperates with nephrin to transduce a signal that induces actin polymerization. Mol Cell Biol. 2007;27(24):8698–712.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Donoviel DB, Freed DD, Vogel H, Potter DG, Hawkins E, Barrish JP, Mathur BN, Turner CA, Geske R, Montgomery CA, Starbuck M, Brandt M, Gupta A, Ramirez-Solis R, Zambrowicz BP, Powell DR. Proteinuria and perinatal lethality in mice lacking NEPH1, a novel protein with homology to NEPHRIN. Mol Cell Biol. 2001;21(14):4829–36.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Ciani L, Patel A. Allen ND, ffrench-Constant C. Mice lacking the giant protocadherin mFAT1 exhibit renal slit junction abnormalities and a partially penetrant cyclopia and anophthalmia phenotype. Mol Cell Biol. 2003;23(10):3575–82.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Goode NP, Shires M, Khan TN, Mooney AF. Expression of alpha-actinin-4 in acquired human nephrotic syndrome: a quantitative immunoelectron microscopy study. Nephrol Dial Transplant. 2004;19(4):844–51.

    Article  CAS  PubMed  Google Scholar 

  28. Sun H, Schlondorff J, Higgs HN, Pollak MR. Inverted formin 2 regulates actin dynamics by antagonizing Rho/diaphanous-related formin signaling. J Am Soc Nephrol. 2013;24(6):917–29.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Kriz W, Gretz N, Lemley KV. Progression of glomerular diseases: is the podocyte the culprit? Kidney Int. 1998;54(3):687–97.

    Article  CAS  PubMed  Google Scholar 

  30. Mao J, Zhang Y, Du L, Dai Y, Yang C, Liang L. Expression profile of nephrin, podocin, and CD2AP in Chinese children with MCNS and IgA nephropathy. Pediatr Nephrol. 2006;21(11):1666–75.

    Article  PubMed  Google Scholar 

  31. Agrawal V, Prasad N, Jain M, Pandey R. Reduced podocin expression in minimal change disease and focal segmental glomerulosclerosis is related to the level of proteinuria. Clin Exp Nephrol. 2013;17(6):811–8.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by grants from the Sigrid Juselius Foundation, the Pediatric Research Foundation and Helsinki University Central Hospital Research Fund. We warmly thank Tuike Helmiö for excellent technical assistance.

Conflict of interest

The authors have declared that no conflict of interest exists.

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Authors and Affiliations

  1. Children’s Hospital, University of Helsinki and Helsinki University Central Hospital, Tukholmankatu 8, 00290, Helsinki, Finland

    Maija Suvanto, Timo Jahnukainen & Hannu Jalanko

  2. Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland

    Marjo Kestilä

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  1. Maija Suvanto
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  2. Timo Jahnukainen
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  4. Hannu Jalanko
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Correspondence to Maija Suvanto.

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Suvanto, M., Jahnukainen, T., Kestilä, M. et al. Podocyte proteins in congenital and minimal change nephrotic syndrome. Clin Exp Nephrol 19, 481–488 (2015). https://doi.org/10.1007/s10157-014-1020-z

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  • DOI: https://doi.org/10.1007/s10157-014-1020-z

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