Skip to main content

Advertisement

SpringerLink
Log in

Defective activation of the MAPK/ERK pathway, leading to PARP1 and DNMT1 dysregulation, is a common defect in IgA nephropathy and Henoch-Schönlein purpura

  • Original Article
  • Published:
Journal of Nephrology Aims and scope Submit manuscript

Abstract

Studies on IgA nephropathy (IgAN) have identified, through GWAS, linkage analysis, and pathway scanning, molecular defects in familial and sporadic IgAN patients. In our previous study, we identified a novel variant in the SPRY2 gene that segregates with the disease in one large family. The functional characterization of this variant led us to discover that the MAPK/ERK pathway was defective not only in this family, but also in two sporadic IgAN patients wild type for SPRY2. In the present study, we have deepened the molecular analysis of the MAPK/ERK pathway and extended our evaluation to a larger cohort of sporadic patients and to one additional family. We found that the ERK pathway is defective in IgAN patients and in patients affected by another IgA-mediated disorder, Henoch-Schönlein purpura (HSP). Furthermore, we found that two other proteins, PARP1 and DNMT1, respectively involved in DNA repair and in antibody class switching and methylation maintenance duties, were critically downregulated in IgAN and HSP patients. This study opens up the possibility that defective ERK activation, in some patients, leads to PARP1 and DNMT1 downregulation suggesting that IgAN could be the consequence of a dysregulated epigenetic maintenance leading to the upregulation of several genes. In particular, PARP1 could be used as a potential biomarker for the disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Donadio JV, Grande JP (2002) IgA nephropathy. N Engl J Med 347:738–748. https://doi.org/10.1056/NEJMra020109

    Article  CAS  PubMed  Google Scholar 

  2. Pozzi C (2016) Treatment of IgA nephropathy. J Nephrol 29:21–25. https://doi.org/10.1007/s40620-015-0248-3

    Article  CAS  PubMed  Google Scholar 

  3. Pozzi C, Sarcina C, Ferrario F (2016) Treatment of IgA nephropathy with renal insufficiency. J Nephrol 29:551–558. https://doi.org/10.1007/s40620-015-0257-2

    Article  CAS  PubMed  Google Scholar 

  4. Floege J (2011) The pathogenesis of IgA nephropathy: what is new and how does it change therapeutic approaches? Am J Kidney Dis 58:992–1004

    Article  CAS  Google Scholar 

  5. Suzuki H, Kiryluk K, Novak J et al (2011) The pathophysiology of IgA nephropathy. J Am Soc Nephrol 22:1795–1803

    Article  CAS  Google Scholar 

  6. Hiki Y, Hori H, Yamamoto K et al (2015) Specificity of two monoclonal antibodies against a synthetic glycopeptide, an analogue to the hypo-galactosylated IgA1 hinge region. J Nephrol 28:181–186. https://doi.org/10.1007/s40620-014-0118-4

    Article  CAS  PubMed  Google Scholar 

  7. Nakagawa Y, Saito K, Nishi S et al (1999) Recurrence of IgA nephropathy 17 months after renal transplantation in the allograft transmitted thin basement membrane disease (TBMD) from donor. Clin Transpl 13(Suppl 1):59–62

    Google Scholar 

  8. Sanfilippo F, Croker BP, Bollinger RR (1982) Fate of four cadaveric donor renal allografts with mesangial IgA deposits. Transplantation 33:370–376

    Article  CAS  Google Scholar 

  9. Iwata Y, Wada T, Uchiyama A et al (2006) Remission of IgA nephropathy after allogeneic peripheral blood stem cell transplantation followed by immunosuppression for acute lymphocytic leukemia. Intern Med 45:1291–1295

    Article  Google Scholar 

  10. Suzuki Y, Suzuki H, Nakata J et al (2011) Pathological role of tonsillar B cells in IgA nephropathy. Clin Dev Immunol 2011:639074

    Article  Google Scholar 

  11. Milillo A, La Carpia F, Costanzi S et al (2015) A SPRY2 mutation leading to MAPK/ERK pathway inhibition is associated with an autosomal dominant form of IgA nephropathy. Eur J Hum Genet. https://doi.org/10.1038/ejhg.2015.52

    Article  PubMed  PubMed Central  Google Scholar 

  12. Davin JC (2011) Henoch-Schönlein purpura nephritis: pathophysiology, treatment, and future strategy. Clin J Am Soc Nephrol 6:679–689

    Article  Google Scholar 

  13. Xu K, Zhang L, Ding J et al (2017) Value of the Oxford classification of IgA nephropathy in children with Henoch-Schönlein purpura nephritis. J Nephrol. https://doi.org/10.1007/s40620-017-0457-z

    Article  PubMed  Google Scholar 

  14. Gorelik G, Fang JY, Wu A et al (2007) Impaired T cell protein kinase C delta activation decreases ERK pathway signaling in idiopathic and hydralazine-induced lupus. J Immunol 179:5553–5563

    Article  CAS  Google Scholar 

  15. Tordai A, Franklin RA, Patel H et al (1994) Cross-linking of surface IgM stimulates the Ras/Raf-1/MEK/MAPK cascade in human B lymphocytes. J Biol Chem 269:7538–7543

    CAS  PubMed  Google Scholar 

  16. Akhiani AA, Werlenius O, Aurelius J et al (2014) Role of the ERK pathway for oxidant-induced parthanatos in human lymphocytes. PLoS One 9:e89646

    Article  Google Scholar 

  17. Hazzalin CA, Mahadevan LC (2002) MAPK-regulated transcription: a continuously variable gene switch? Nat Rev Mol Cell Biol 3:30–40. https://doi.org/10.1038/nrm715

    Article  CAS  PubMed  Google Scholar 

  18. Ambrose HE, Willimott S, Beswick RW et al (2009) Poly(ADP-ribose) polymerase-1 (Parp-1)-deficient mice demonstrate abnormal antibody responses. Immunology 127:178–186. https://doi.org/10.1111/j.1365-2567.2008.02921.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Deng C, Lu Q, Zhang Z et al (2003) Hydralazine may induce autoimmunity by inhibiting extracellular signal-regulated kinase pathway signaling. Arthr Rheum 48:746–756

    Article  CAS  Google Scholar 

  20. Reale A, Matteis G, De Galleazzi G et al (2005) Modulation of DNMT1 activity by ADP-ribose polymers. Oncogene 24:13–19. https://doi.org/10.1038/sj.onc.1208005

    Article  CAS  PubMed  Google Scholar 

  21. Kauppinen TM, Chan WY, Suh SW et al (2006) Direct phosphorylation and regulation of poly(ADP-ribose) polymerase-1 by extracellular signal-regulated kinases 1/2. Proc Natl Acad Sci 103:7136–7141. https://doi.org/10.1073/pnas.0508606103

    Article  CAS  PubMed  Google Scholar 

  22. Seidl T, Whittall T, Babaahmady K, Lehner T (2012) B-cell agonists up-regulate AID and APOBEC3G deaminases, which induce IgA and IgG class antibodies and anti-viral function. Immunology 135:207–215. https://doi.org/10.1111/j.1365-2567.2011.03524.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Schrader CE, Edelmann W, Kucherlapati R, Stavnezer J (1999) Reduced isotype switching in splenic B cells from mice deficient in mismatch repair enzymes. J Exp Med 190:323–330

    Article  CAS  Google Scholar 

  24. Zhang Y, Zhao M, Sawalha AH et al (2013) Impaired DNA methylation and its mechanisms in CD4+ T cells of systemic lupus erythematosus. J Autoimmun 41:92–99. https://doi.org/10.1016/j.jaut.2013.01.005

    Article  CAS  PubMed  Google Scholar 

  25. Kim HS, Song M-C, Kwak IH et al (2003) Constitutive induction of p-Erk1/2 accompanied by reduced activities of protein phosphatases 1 and 2A and MKP3 due to reactive oxygen species during cellular senescence. J Biol Chem 278:37497–37510. https://doi.org/10.1074/jbc.M211739200

    Article  CAS  PubMed  Google Scholar 

  26. Smith SM, Tokuda S, Tsukamoto H (1992) Mucosal immune dysfunction associated with alcoholic IgA nephropathy. Clin Immunol Immunopathol 64:205–209

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank Maurizio Genuardi for critical reading of the manuscript and the rest of the Institute of Genomic Medicine for sharing discussions and ideas. We would like to thank the patients young and older for their participation to this study.

Funding

This study was funded by internal funds of the Institute of Genomic Medicine.

Author information

Authors and Affiliations

  1. Istituto di Medicina Genomica, Università Cattolica del Sacro Cuore, 00168, Roma, Italy

    Annamaria Milillo, Clelia Molinario, Francesco La Greca, Giovanni Gambaro, Fiorella Gurrieri & Eugenio Sangiorgi

  2. Division of Nephrology and Dialysis Columbus Fondazione Policlinico Gemelli, 00168, Roma, Italy

    Stefano Costanzi, Gisella Vischini & Giovanni Gambaro

  3. Department of Pathology and Cell Biology, Columbia University Medical Center New York, New York, USA

    Francesca La Carpia

  4. Division of Pediatrics, Gemelli University Hospital, 00168, Roma, Italy

    Donato Rigante

Authors
  1. Annamaria Milillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Clelia Molinario
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stefano Costanzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gisella Vischini
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Francesca La Carpia
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Francesco La Greca
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Donato Rigante
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Giovanni Gambaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Fiorella Gurrieri
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Eugenio Sangiorgi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Fiorella Gurrieri or Eugenio Sangiorgi.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical statement

This project was authorized by the Comitato di Bioetica of the Catholic University (#27321/13).

Informed consent

Informed consent was obtained from all participants to this study.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Milillo, A., Molinario, C., Costanzi, S. et al. Defective activation of the MAPK/ERK pathway, leading to PARP1 and DNMT1 dysregulation, is a common defect in IgA nephropathy and Henoch-Schönlein purpura. J Nephrol 31, 731–741 (2018). https://doi.org/10.1007/s40620-018-0482-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40620-018-0482-6

Keywords

Search

Navigation