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COSMC expression as a predictor of remission in IgA nephropathy

  • Nephrology - Original Paper
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Abstract

Purpose

The impact of core 1,3-galactosyltransferase-specific molecular chaperon (COSMC) gene expression and methylation profile on clinical progression of IgA nephropathy (IgAN) is unclear. The aim of this study was to determine the clinical significance and the relation of the COSMC gene expression and methylation pattern with the progression of IgAN.

Methods

Thirty-nine biopsy-confirmed IgAN patients, 11 healthy relatives and 20 healthy controls were recruited. The COSMC mRNA levels and methylation profile of COSMC gene promoter were measured using the quantitative real-time PCR. The galactose-deficient IgA1 (Gd-IgA1) levels were measured using ELISA in serum and cell culture supernatant. The effect of IL-4 and AZA on COSMC expression and methylation and the correlation of COSMC gene expression and methylation levels with baseline kidney function tests, histology and long-term outcomes were examined.

Results

The mean COSMC mRNA level was significantly lower, and serum Gd-IgA1 level was higher in IgAN patients compared with the control groups (p < 0.001, and p =  < 0.001, respectively). The COSMC mRNA levels were correlated with intensity of hematuria (r = − 0.41, p = 0.009), serum creatinine level (r = − 0.37, p = 0.002) and eGFR (r = 0.36, p = 0.002). The COSMC methylation levels were correlated with age (r = 0.25, p = 0.04) and baseline eGFR (r = − 0.326, p = 0.006). Twenty IgAN patients (51.3%) reached to complete (5, 12.8%) or partial remission (15, 38.5%) after a median of 34.5 months (IQR, 13.75–71). In multivariable Cox regression analysis, COSMC mRNA expression (adjusted HR (aHR) 1.871, 95% CI 1.287–2.722, p = 0.001) and Oxford T score (aHR 0.355, 95% CI 0.146–0.859, p = 0.022) predicted the remission.

Conclusion

COSMC mRNA level is a novel biomarker candidate to predict the remission in IgAN patients.

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References

  1. Stanley JC, Deng H (2020) Progress in pathogenesis of immunoglobin A nephropathy. Cureus 12:1–11. https://doi.org/10.7759/cureus.8789

    Article  Google Scholar 

  2. Kiryluk K, Li Y, Scolari F, Sanna-Cherchi S et al (2014) Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens. Nat Genet 46:1187–1196. https://doi.org/10.1038/ng.3118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Gharavi AG, Kiryluk K, Choi M et al (2011) Genome-wide association study identifies susceptibility loci for IgA nephropathy. Nat Genet 43:321–327. https://doi.org/10.1038/ng.787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Temurhan S, Akgul SU, Caliskan Y et al (2017) A novel biomarker for post-transplant recurrent IgA nephropathy. Transpl Proc 49:541–545. https://doi.org/10.1016/j.transproceed.2017.02.003

    Article  CAS  Google Scholar 

  5. Caliskan Y, Kiryluk K (2014) Novel biomarkers in glomerular disease. Adv Chronic Kidney Dis 21:205–216. https://doi.org/10.1053/j.ackd.2013.12.002

    Article  PubMed  PubMed Central  Google Scholar 

  6. Gharavi AG, Moldoveanu Z, Wyatt RJ et al (2008) Aberrant IgA1 glycosylation is inherited in familial and sporadic IgA nephropathy. J Am Soc Nephrol 19:1008–1014. https://doi.org/10.1681/ASN.2007091052

    Article  PubMed  PubMed Central  Google Scholar 

  7. Lai KN, Tang SC, Schena FP et al (2016) IgA nephropathy. Nat Rev Dis Primers 2:16001. https://doi.org/10.1038/nrdp.2016.1

    Article  PubMed  Google Scholar 

  8. Rajasekaran A, Julian BA, Rizk DV (2021) IgA Nephropathy: An Interesting Autoimmune Kidney Disease. Am J Med Sci 361:176–194. https://doi.org/10.1016/j.amjms.2020.10.003

    Article  PubMed  Google Scholar 

  9. Robert T, Berthelot L, Cambier A et al (2015) Molecular Insights into the Pathogenesis of IgA Nephropathy. Trends Mol Med 21:762–775. https://doi.org/10.1016/j.molmed.2015.10.003

    Article  CAS  PubMed  Google Scholar 

  10. Suzuki H, Moldoveanu Z, Hall S et al (2008) IgA1-secreting cell lines from patients with IgA nephropathy produce aberrantly glycosylated IgA1. J Clin Invest 118:629–639. https://doi.org/10.1172/JCI33189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Mi R, Song L, Wang Y et al (2016) Epigenetic silencing of the chaperone Cosmc in human leukocytes expressing Tn antigen. J Biol Chem 287:41523–41533. https://doi.org/10.1074/jbc.M112.371989

    Article  CAS  Google Scholar 

  12. Fuss IJ, Kanof ME, Smith PD et al (2009) Isolation of whole mononuclear cells from peripheral blood and cord blood. In: Coligan JE (eds) Current protocols in immunology.1st edn. Wiley, New York. https://doi.org/10.1002/0471142735.im0701s85.

  13. Esteller M (2007) Epigenetic gene silencing in cancer: the DNA hypermethylome. Hum Mol Genet 16:50–59. https://doi.org/10.1093/hmg/ddm018

    Article  CAS  Google Scholar 

  14. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data usingreal-time quantitative PCR and the 2−ΔΔCT method. Methods 25:402–408. https://doi.org/10.1006/meth.2001.1262

    Article  CAS  PubMed  Google Scholar 

  15. Yasutake J, Suzuki Y, Suzuki H et al (2015) Novellectin-in dependent approach to detect galactose-deficient IgA1 in IgA nephropathy. Nephrol Dial Transpl 30:1315–1321. https://doi.org/10.1093/ndt/gfv221

    Article  CAS  Google Scholar 

  16. Barbour SJ, Espino-Hernandez G, Reich HN et al (2016) The MEST score provides earlier risk prediction in lgA nephropathy. Kidney Int 89:167–175. https://doi.org/10.1038/ki.2015.322

    Article  CAS  PubMed  Google Scholar 

  17. Trimarchi H, Barratt J, Cattran DC et al (2017) Oxford classification of IgA nephropathy 2016: an update from the IgA Nephropathy Classification Working Group. Kid Int 91:1014–1021. https://doi.org/10.1016/j.kint.2017.02.003

    Article  Google Scholar 

  18. Canney M, Barbour SJ, Zheng Y et al (2021) International IgA nephropathy network; ınternational IgA nephropathy network ınvestigators. quantifying duration of proteinuria remission and association with clinical outcome in IgA nephropathy. J Am Soc Nephrol 32:436–447. https://doi.org/10.1681/ASN.20200.30349

    Article  CAS  PubMed  Google Scholar 

  19. Hatchwell E, Greally JM (2007) The potential role of epigenomic dysregulation in complex human disease. Trends Genet 3:588–595. https://doi.org/10.1016/j.tig.2007.08.010

    Article  CAS  Google Scholar 

  20. Yeo SC, Cheung CK, Barratt J (2018) New insights into the pathogenesis of IgA nephropathy. Pediatr Nephrol 33:763–777. https://doi.org/10.1007/s00467-017-3699-z

    Article  PubMed  Google Scholar 

  21. Ju T, Cummings RD (2002) A unique molecular chaperone cosmc required for activity of the mammalian core 1 β-galactosyltransferase. Proc Natl Acad Sci USA 99:16613–16618. https://doi.org/10.1073/pnas.262438199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Qin W, Zhou Q, Yang LC et al (2005) Peripheral B lymphocyte β1,3-galactosyltransferase and chaperone expression in immunoglobulin A nephropathy. J Intern Med 258:467–477. https://doi.org/10.1111/j.1365-2796.2005.01558.x

    Article  CAS  PubMed  Google Scholar 

  23. Sun Q, Zhang Z, Zhang H et al (2016) Aberrant IgA1 glycosylation in IgA nephropathy: a systematic review. PLoS ONE 11:e0166700. https://doi.org/10.1371/journal.pone.0166700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Xie L, Tan C, Fan J et al (2016) Mycophenolicacid reverses IgA1 aberrant glycosylation through up-regulating Cosmc expression in IgA nephropathy. Int Urol Nephrol 45:571–579. https://doi.org/10.1007/s11255-012-0313-y

    Article  CAS  Google Scholar 

  25. Qinn W, Zhong X, Fan JM et al (2008) External suppression causes the low expression of the Cosmc gene in IgA nephropathy. Nephrol Dial Transpl 23:1608–1614. https://doi.org/10.1093/ndt/gfm781

    Article  CAS  Google Scholar 

  26. Sun Q, Zhang J, Zhou N et al (2015) DNA methylation in Cosmc promoter region and aberrantly glycosylated IgA1 associated with pediatric IgA nephropathy. PLoS ONE 10:e0112305. https://doi.org/10.1371/journal.pone.0112305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Qin W, Zhong X, Fan JM et al (2011) Effect of methylation modification on the expression of Cosmc gene in peripheral B lymphocyte of IgA nephropathy patients. Sichuan Da Xue Xue Bao Yi Xue Ban 42:762–765

    CAS  PubMed  Google Scholar 

  28. Sun Q, Lan J, Zhang H et al (2020) MicroRNA-196b targets COSMC in pediatric IgA nephropathy. Mol Med Rep 21:2260–2266. https://doi.org/10.3892/mmr.2020.11015

    Article  CAS  PubMed  Google Scholar 

  29. He L, Peng Y, Liu H et al (2013) Activation of the interleukin-4/signal transducer and activator of transcription 6 signaling pathway and homeodomain-interacting protein kinase 2 production by tonsillar mononuclear cells in IgA nephropathy. Am J Nephrol 38:321–332. https://doi.org/10.1159/000355393

    Article  CAS  PubMed  Google Scholar 

  30. Yamada K, Kobayashi N, Ikeda T et al (2010) Down-regulation of core 1 β1,3-galactosyltransferase and Cosmc by Th2 cytokine alters O-glycosylation of IgA1. Nephrol Dial Transpl 25:3890–3897. https://doi.org/10.1093/ndt/gfq325

    Article  CAS  Google Scholar 

  31. Maixnerova D, Ling C, Hall S et al (2019) Correction: galactose-deficient IgA1 and the corresponding IgG autoantibodies predict IgA nephropathy progression. PLoS ONE 14:e0219947. https://doi.org/10.1371/journal.pone.0219947

    Article  PubMed  PubMed Central  Google Scholar 

  32. Bagchi S, Lingaiah R, Mani K et al (2019) Significance of serum galactose deficient IgA1 as a potential biomarker for IgA nephropathy: a case control study. PLoS ONE 14:e0214256. https://doi.org/10.1371/journal.pone.0214256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Caliskan Y, Demir E, Karatay E et al (2021) Oxidative stress and macrophage infiltration in IgA nephropathy. J Nephrol. https://doi.org/10.1007/s40620-021-01196-7

    Article  PubMed  Google Scholar 

  34. Nguyen C, König K, Tam FWK et al (2018) Higher serum galactose-deficient immunoglobulin A1 concentration is associated with stronger mesangial cellular inflammatory response and more severe histologic findings in immunoglobulin A nephropathy. Clin Kidney J 12:232–238. https://doi.org/10.1093/ckj/sfy068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Tan M, Li W, Zou G et al (2015) Clinicopathological features and outcomes of IgA nephropathy with hematuria and/or minimal proteinuria. Kidney Blood Press Res 40:200–206. https://doi.org/10.1159/000368495

    Article  CAS  PubMed  Google Scholar 

  36. Goto M, Wakai K, Kawamura T et al (2009) A scoring system to predict renal outcome in IgA nephropathy: a nationwide 10-year prospective cohort study. Nephrol Dial Transpl 24:3068–3074. https://doi.org/10.1093/ndt/gfp273

    Article  Google Scholar 

  37. Maixnerova D, Neprasova M, Skibova J et al (2014) IgA nephropathy in Czech patients—are we able reliably predict the outcome? Kidney Blood Press Res 39:555–562. https://doi.org/10.1159/000368467

    Article  CAS  PubMed  Google Scholar 

  38. Caliskan Y, Ozluk Y, Celik D et al (2016) The Clinical Significance of Uric Acid and Complement Activation in the Progression of IgA Nephropathy. Kidney Blood Press Res 41:148–157. https://doi.org/10.1159/000443415

    Article  CAS  PubMed  Google Scholar 

  39. Bartosik LP, Lajoie G, Sugar L et al (2001) Predicting progression in IgA nephropathy. Am J Kidney Dis 38:728–735. https://doi.org/10.1053/ajkd.2001.27689

    Article  CAS  PubMed  Google Scholar 

  40. Donadio JV, Bergstralh EJ, Grande JP et al (2002) Proteinuria patterns and their association with subsequent end-stage renal disease in IgA nephropathy. Nephrol Dial Transpl 17:1197–1203. https://doi.org/10.1093/ndt/17.7.1197

    Article  CAS  Google Scholar 

  41. Artan AS, Mirioglu S, Demir E et al (2021) Lower baseline eGFR levels and IgA nephropathy prediction tool. Nephrology (Carlton). https://doi.org/10.1111/nep.13934

    Article  PubMed  Google Scholar 

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Acknowledgements

This Project was supported by the Istanbul University Scientific Research Unit (Project ID:55868).

Funding

The authors have no relevant financial or non-financial interests to disclose.

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Authors and Affiliations

  1. Department of Medical Biology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey

    Sebahat Usta Akgul, Cigdem Kekik Cinar, Rasimcan Meral, Sonay Temurhan & Fatma Savran Oguz

  2. Transplant Immunology Research Center of Excellence, Koç University, Istanbul, Turkey

    Sebahat Usta Akgul

  3. Division of Nephrology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Capa/Fatih, Istanbul, Turkey

    Yasar Caliskan

  4. Division of Nephrology, Saint Louis University School of Medicine, Saint Louis, MO, USA

    Yasar Caliskan & Erol Demir

  5. Department of Nephrology, Health Sciences University, Haseki Training and Research Hospital, Istanbul, Turkey

    Egemen Cebeci

  6. Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey

    Yasemin Ozluk

  7. Department of Medical Biology and Genetics, Demiroglu Science University, Istanbul, Turkey

    Filiz Aydin

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  1. Sebahat Usta Akgul
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Contributions

SUA, CKC, YC and FSO participated in study design, acquisition of data and regulatory approvals, data analysis, and writing of the paper. YO assessed all biopsy samples and participated in interpretation and writing of the paper. SUA, FA, ST and RM measured serum levels of Gd-IgA1 and levels of COSMC mRNA and DNA methylation and also participated in interpretation and writing of the paper. YC, ED and EC reviewed the patient charts and participated in data interpretation and writing of the paper.

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Correspondence to Sebahat Usta Akgul.

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The research was approved by Faculty of Medicine Institutional Review Board (approval number: 2015-1506).

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Akgul, S.U., Cinar, C.K., Caliskan, Y. et al. COSMC expression as a predictor of remission in IgA nephropathy. Int Urol Nephrol 55, 1033–1044 (2023). https://doi.org/10.1007/s11255-022-03376-1

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