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A podocyte view of membranous nephropathy: from Heymann nephritis to the childhood human disease

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Abstract

Membranous nephropathy (MN) is characterized by an accumulation of immune deposits on the subepithelial side of the glomerular basement membrane, which results in complement activation and proteinuria. Since 2002, several major antigens of the podocyte have been identified in human MN, the first one being neutral endopeptidase (NEP), the alloantigen involved in neonatal cases of MN that occur in newborns from NEP-deficient mothers. This discovery opened the field to the major advances that have occurred since then in the pathophysiology and treatment of MN. It is remarkable that experimental models such as Heymann nephritis and cationic bovine serum albumin-induced MN in the rabbit predicted the pathomechanisms of the human glomerulopathy. The podocyte is at the center of the pathogenesis of MN either by providing a source of endogenous antigens or by creating an environment favorable to deposition and accumulation of immune complexes containing exogenous (non-podocyte) antigens. The podocyte is also a victim of complement activation and antibody blocking activity against enzymes or receptors. A search for innovative drugs aimed at protecting this cell against complement activation and the effects of prolonged ER stress has become a priority.

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References

  1. Adler SG et al (1983) Electrical charge. Its role in the pathogenesis and prevention of experimental membranous nephropathy in the rabbit. J Clin Invest 71:487–499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Allegri L et al (1986) Polyvalent antigen-antibody interactions are required for the formation of electron-dense immune deposits in passive Heymann’s nephritis. Am J Pathol 125:1–6

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Alting AC, Meijer RJ, van Beresteijn EC (1997) Incomplete elimination of the ABBOS epitope of bovine serum albumin under simulated gastrointestinal conditions of infants. Diabetes Care 20:875–880

    Article  CAS  PubMed  Google Scholar 

  4. Assmann KJ et al (1983) Membranous glomerulonephritis in the mouse. Kidney Int 24:303–312

    Article  CAS  PubMed  Google Scholar 

  5. Assmann KJ et al (1985) Comparison of antigenic targets involved in antibody-mediated membranous glomerulonephritis in the mouse and rat. Am J Pathol 121:112–122

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Assmann KJ et al (1989) Involvement of an antigen distinct from the Heymann antigen in membranous glomerulonephritis in the mouse. Lab Investig 60:138–146

    CAS  PubMed  Google Scholar 

  7. Avner ED, Harmon WE, Niaudet P, Yoshikawa N, Emma F, Goldstein SL (eds) (2016) Pediatric nephrology, 7th edn. Springer, New-York, p 1055–1075

  8. Beck LH Jr et al (2009) M-type phospholipase A2 receptor as target antigen in idiopathic MN. N Engl J Med 361:11–21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Biemesderfer D (2006) Regulated intramembrane proteolysis of megalin: linking urinary protein and gene regulation in proximal tubule? Kidney Int 69:1717–1721

    Article  CAS  PubMed  Google Scholar 

  10. Bohana-Kashtan O, Ziporen L, Donin N et al (2004) Cell signals transduced by complement. Mol Immunol 41:583–597

    Article  CAS  PubMed  Google Scholar 

  11. Border WA et al (1982) Induction of membranous nephropathy in rabbits by administration of an exogenous cationic antigen. J Clin Invest 69:451–461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Brooks DA (1999) Immune response to enzyme replacement therapy in lysosomal storage disorder patients and animal models. Mol Genet Metab 68:268–275

    Article  CAS  PubMed  Google Scholar 

  13. Chen A, Frank R, Vento S et al (2007) Idiopathic membranous nephropathy in pediatric patients: presentation, response to therapy, and long-term outcome. BMC Nephrol 6:8–11

    Google Scholar 

  14. Chen JS, Chen A, Chang LC et al (2004) Mouse model of membranous nephropathy induced by cationic bovine serum albumin: antigen dose-response relations and strain differences. Nephrol Dial Transplant 19:2721–2728

    Article  CAS  PubMed  Google Scholar 

  15. Couser WG et al (1978) Experimental glomerulonephritis in the isolated perfused rat kidney. J Clin Invest 62:1275–1287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cunningham PN, Quigg RJ (2005) Contrasting roles of complement activation and its regulation in membranous nephropathy. J Am Soc Nephrol 16:1214–1222

    Article  CAS  PubMed  Google Scholar 

  17. Cybulsky AV (2010) Endoplasmic reticulum stress in proteinuric kidney disease. Kidney Int 7:187–193

    Article  Google Scholar 

  18. Cybulsky AV (2013) The intersecting roles of endoplasmic reticulum stress, ubiquitin- proteasome system, and autophagy in the pathogenesis of proteinuric kidney disease. Kidney Int 84:25–33

    Article  CAS  PubMed  Google Scholar 

  19. Cybulsky AV, Quigg RJ, Salant DJ (2005) Experimental membranous nephropathy redux. Am J Physiol Ren Physiol 289:F660–F671

    Article  CAS  Google Scholar 

  20. Davis PJ, Williams SC (1998) Protein modification by thermal processing. Allergy 53:102–105

    Article  CAS  PubMed  Google Scholar 

  21. Debiec H et al (2002) Antenatal membranous glomerulonephritis due to anti-neutral endopeptidase antibodies. N Engl J Med 346:2053–2060

    Article  PubMed  Google Scholar 

  22. Debiec H et al (2004) Role of truncating mutations in MME gene in feto-maternal allo-immunization and neonatal glomerulopathies. Lancet 364:1252–1259

    Article  CAS  Google Scholar 

  23. Debiec H, Lefeu F, Kemper MJ et al (2011) Early-childhood membranous nephropathy due to cationic bovine serumalbumin. N Engl J Med 364:2101–2110

    Article  CAS  PubMed  Google Scholar 

  24. Debiec H, Valayannopoulos V, Boyer O et al (2014) Allo-immune membranous nephropathy and recombinant aryl sulfatase replacement therapy: a need for tolerance induction therapy. J Am Soc Nephrol 25:675–680

    Article  CAS  PubMed  Google Scholar 

  25. Dussaule JC, Stefanski A, Bea ML et al (1993) Characterization of neutral endopeptidase in vascular smooth muscle cells of rabbit renal cortex. Am J Phys 264:F45–F52

    CAS  Google Scholar 

  26. Friedrich C, Endlich N, Kriz W et al (2006) Podocytes are sensitive to fluid shear stress in vitro. Am J Physiol Ren Physiol 291:F856–F865

    Article  CAS  Google Scholar 

  27. Giardino L et al (2009) Podocyte glutamatergic signaling contributes to the function of the glomerular filtration barrier. J Am Soc Nephrol 20:1929–1940

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Harmatz P, Giugliani R, Schwartz I et al (2006) Enzyme replacement therapy for mucopolysaccharidosis VI: a phase 3, randomized, double-blind, placebo-controlled, multinational study of recombinant human N-acetylgalactosamine 4-sulfatase (recombinant human arylsulfatase B or rhASB) and follow-on, open-label extension study. J Pediatr 148:533–539

    Article  CAS  PubMed  Google Scholar 

  29. Hendriksz CJ, Giugliani R, Harmatz P et al (2013) Design, baseline characteristics, and early findings of the MPS VI (mucopolysaccharidosis VI) Clinical Surveillance Program (CSP). J Inherit Metab Dis 36:373–384

    Article  PubMed  Google Scholar 

  30. Heymann W et al (1959) Production of nephrotic syndrome in rats by Freund’s adjuvants and rat kidney suspension. Proc Soc Exp Biol Med 100:660–664

    Article  CAS  PubMed  Google Scholar 

  31. Hu P, Xuan Q, Hu B et al (2013) Anti-neutral endopeptidase, natriuretic peptides disarrangement, and proteinuria onset in membranous nephropathy. Mol Biol Rep 40:2963–2967

    Article  CAS  PubMed  Google Scholar 

  32. Hunley TE, Corzo D, Dudek M et al (2004) Nephrotic syndrome complicating alpha-glucosidase replacement therapy for Pompe disease. Pediatrics 114:e532–e535

    Article  PubMed  Google Scholar 

  33. Kerjaschki D (2000) Pathogenetic concepts of membranous glomerulopathy (MGN). J Nephrol 13:S96–S100

    PubMed  Google Scholar 

  34. Kerjaschki D, Exner M, Ullrich R et al (1997) Pathogenic antibodies inhibit the binding of apolipoproteins to megalin/gp330 in passive Heymann nephritis. J Clin Invest 100:2303–2309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kerjaschki D, Farquhar MG (1982) The pathogenic antigen of Heymann nephritis is a membrane glycoprotein of the renal proximal tubule brush border. Proc Natl Acad Sci 79:5557–5561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kerjaschki D, Farquhar MG (1983) Immunocytochemical localization of the Heymann nephritis antigen (gp330) in glomerular epithelial cells of normal Lewis rats. J Exp med 157:667–686

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kerjaschki D, Miettinen A, Farquhar MG (1987) Initial events in the formation of immune deposits in passive Heymann nephritis. gp330-anti-gp330 immune complexes form in epithelial coated pits and rapidly become attached to the glomerular basement membrane. J Exp Med 166:109–128

    Article  CAS  PubMed  Google Scholar 

  38. Kerjaschki D, Schulze M, Binder S et al (1989) Transcellular transport and membrane insertion of the C5b-9 membrane attack complex of complement by glomerular epithelial cells in experimental membranous nephropathy. J Immunol 143:546–552

    CAS  PubMed  Google Scholar 

  39. Kon SP, Coupes B, Short CD et al (1995) Urinary C5b-9 excretion and clinical course in idiopathic human membranous nephropathy. Kidney Int 48:1953–1958

    Article  CAS  PubMed  Google Scholar 

  40. Koren E, Zuckerman LA, Mire-Sluis AR (2002) Immune responses to therapeutic proteins in humans—clinical significance, assessment and prediction. Curr Pharm Biotechnol 3:349–360

    Article  CAS  PubMed  Google Scholar 

  41. Koyama A, Inage H, Kobayashi M et al (1986) Effect of chemical cationization of antigen on glomerular localization of immune complexes in active models of serum sickness nephritis in rabbits. Immunology 58:529–534

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Lebeau C, Debelle FD, Arlt VM et al (2005) Early proximal tubule injury in experimental aristolochic acid nephropathy: functional and histological studies. Nephrol Dial Transplant 20:2321–2332

    Article  PubMed  Google Scholar 

  43. Leenaerts PL, Hall BM, Van Damme BJ et al (1995) Active Heymann nephritis in complement component C6 deficient rats. Kidney Int 47:1604–1614

    Article  CAS  PubMed  Google Scholar 

  44. Lewko B, Goos M, Latawiec E et al (2006) Regulation of cGMP synthesis in cultured podocytes by vasoactive hormones. J Physiol Pharmacol 57:599–610

    CAS  PubMed  Google Scholar 

  45. Lu B, Figini M, Emanueli C et al (1997) The control of microvascular per- meability and blood pressure by neutral endopeptidase. Nat Med 3:904–907

    Article  CAS  PubMed  Google Scholar 

  46. Meyer TN et al (2007) A new mouse model of immune-mediated podocyte injury. Kidney Int 72:841–852

    Article  CAS  PubMed  Google Scholar 

  47. Meyer-Schwesinger C et al (2011) Nephrotic syndrome and subepithelial deposits in a mouse model of immune-mediated anti-podocyte glomerulonephritis. J Immunol 187:3218–3229

    Article  CAS  PubMed  Google Scholar 

  48. Meyer-Schwesinger C, Meyer TN, Münster S et al (2009) A new role for the neuronal ubiquitin C-terminal hydrolase-L1 (UCH-L1) in podocyte process formation and podocyte injury in human glomerulopathies. J Pathol 217:452–464

    Article  CAS  PubMed  Google Scholar 

  49. Morton MJ et al (2004) Human podocytes possess a stretch-sensitive, Ca2+-activated K+ channel: potential implications for the control of glomerular filtration. J Am Soc Nephrol 15:2981–2987

    Article  PubMed  Google Scholar 

  50. Moskovich O, Fishelson Z (2000) Live cell imaging of outward and inward vesiculation induced by the complement c5b-9 complex. J Biol Chem 28:29977–29986

    Google Scholar 

  51. Namba T et al (2000) Inhibition of the human intermediate conductance Ca(2+)-activated K(+) channel, hIK1, by volatile anesthetics. Eur J Pharmacol 395:95–101

    Article  CAS  PubMed  Google Scholar 

  52. Nambi P, Pullen M, Wu HL et al (1999) Down regulation of kidney neutral endopeptidase mRNA, protein and activity during acute renal failure:possible mechanism for ischemia-induced acute renal failure in rats? Mol Cell Biochem 197:53–59

    Article  CAS  PubMed  Google Scholar 

  53. Nangaku M, Shankland SJ, Couser WG (2005) Cellular response to injury in membranous nephropathy. J Am Soc Nephrol 16:1195–1204

    Article  CAS  PubMed  Google Scholar 

  54. Oleinikov AV, Feliz BJ, Makker SP (2000) A small N-terminal 60-kD fragment of gp600 (megalin), the major autoantigen of active Heymann nephritis, can induce a full-blown disease. J Am Soc Nephrol 11:57–64

    CAS  PubMed  Google Scholar 

  55. Raychowdhury R et al (1996) Induction of Heymann nephritis with a gp330/megalin fusion protein. Am J Pathol 148:1613–1623

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Richards SM (2002) Immunologic considerations for enzyme replacement therapy in the treatment of lysosomal storage disorders. Clin Appl Immunol Rev 2:241–253

    Article  CAS  Google Scholar 

  57. Ronco P, Debiec H (2005) Molecular pathomechanisms of membranous nephropathy: from Heymann nephritis to alloimmunization. J Am Soc Nephrol 16:1205–1213

    Article  CAS  PubMed  Google Scholar 

  58. Ronco P, Debiec H (2015) Pathophysiological advances in membranous nephropathy: time for a shift in patient’s care. Lancet 385:1983–1992

    Article  PubMed  Google Scholar 

  59. Ronco P et al (1984) A monoclonal antibody to brush border and passive Heymann nephritis. Clin Exp Immunol 55:319–332

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Saito A et al (1996) Mapping rat megalin: the second cluster of ligand binding repeats contains a 46-amino acid pathogenic epitope involved in the formation of immune deposits in Heymann nephritis. Proc Natl Acad Sci U S A 93:8601–8605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Sanchez C, Fremont S (2003) Consequences of heat treatment and processing of food on the structure and allergenicity of component proteins. Rev Fr Allergol Immunol Clin 43:13–20

    Google Scholar 

  62. Sathe SK, Teuber SS, Roux KH (2005) Effects of food processing on the stability of food allergens. Biotechnol Adv 23:423–429

    Article  CAS  PubMed  Google Scholar 

  63. Schmidt DG, Meijer RJ, Slangen CJ et al (1995) Raising the pH of the pepsin-catalysed hydrolysis of bovine whey proteins increases the antigenicity of the hydrolysates. Clin Exp Allergy 25:1007–1017

    Article  CAS  PubMed  Google Scholar 

  64. Shah P, Tramontano A, Makker SP (2007) Intramolecular spreading in Heymann nephritis. J Am Soc Nephrol 18:3060–3066

    Article  CAS  PubMed  Google Scholar 

  65. Spicer ST, Tran GT, Killingsworth MC et al (2007) Induction of passive Heymann nephritis in complement component 6-deficient PVG rats. J Immunol 179:172–178

    Article  CAS  PubMed  Google Scholar 

  66. Sreedharan R, Mehta DI (2004) Gastrointestinal tract. Pediatrics 113:1044–1050

    PubMed  Google Scholar 

  67. Tegla CA, Cudrici C, Patel S et al (2011) Membrane attack by complement: the assembly and biology of terminal complement complexes. Immunol Res 51:45–60

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Tomas NM, Beck LH Jr, Meyer-Schwesinger C et al (2014) Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. N Engl J Med 371:2277–2287

    Article  PubMed  PubMed Central  Google Scholar 

  69. Tramontano A, Knight T, Vizzuso D, Makker SP (2006) Nested N-terminal megalin fragments induce high-titer autoantibody and attenuated Heymann nephritis. J Am Soc Nephrol 17:1979–1985

    Article  CAS  PubMed  Google Scholar 

  70. Tramontano A, Makker SP (2004) Conformation and glycosylation of a megalin fragment correlate with nephritogenicity in Heymann nephritis. J Immunol 172:2367–2373

    Article  CAS  PubMed  Google Scholar 

  71. Van Damme BJ et al (1978) Experimental glomerulonephritis in the rat induced by antibodies directed against tubular antigens. V. Fixed glomerular antigens in the pathogenesis of heterologous immune complex glomerulonephritis. Lab Investig 38:502–510

    PubMed  Google Scholar 

  72. van Elburg RM, Fetter WP, Bunkers CM et al (2003) Intestinal permeability in relation to birth weight and gestational and postnatal age. Arch Dis Child Fetal Neonatal Ed 88:F52–F55

    Article  PubMed  PubMed Central  Google Scholar 

  73. Vivarelli M, Emma F, Pellé T et al (2015) Genetic homogeneity but IgG subclass-dependent clinical variability of alloimmune membranous nephropathy with anti-neutral endopeptidase antibodies. Kidney Int 87:602–609

    Article  PubMed  Google Scholar 

  74. Wang L, Hong Q, Lv Y et al (2012) Autophagy can repair endoplasmic reticulum stress damage of the passive Heymann nephritis model as revealed by proteomics analysis. J Proteome 75:3866–3876

    Article  CAS  Google Scholar 

  75. Yamazaki H et al (1998) All four putative ligand-binding domains in megalin contain pathogenic epitopes capable of inducing passive Heymann nephritis. J Am Soc Nephrol 9:1638–1644

    CAS  PubMed  Google Scholar 

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Acknowledgments

The research of the authors is supported by grants from the European Research Council (ERC-2012-ADG_20120314; Grant Agreement n° 322947) and the 7th Framework Programme of the European Community, contract 2012-305608 « European Consortium for High-Throughput Research in Rare Kidney Diseases (EURenOmics) ».

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  1. Inserm UMR_S 1155, Hôpital Tenon, 4 rue de la Chine, 75020, Paris, France

    Pierre Ronco & Hanna Debiec

  2. Sorbonne Universités, UPMC Univ Paris 06, 75005, Paris, France

    Pierre Ronco & Hanna Debiec

  3. AP-HP, Hôpital Tenon, Service de Néphrologie et Dialyses, Paris, France

    Pierre Ronco

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Correspondence to Pierre Ronco.

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This article is part of the special issue on Functional Anatomy of the Kidney in Health and Disease in Pflügers Archiv – European Journal of Physiology.

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Ronco, P., Debiec, H. A podocyte view of membranous nephropathy: from Heymann nephritis to the childhood human disease. Pflugers Arch - Eur J Physiol 469, 997–1005 (2017). https://doi.org/10.1007/s00424-017-2007-x

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