SOCS3 is epigenetically up-regulated in steroid resistant nephrotic children

• Authors: Katarzyna Zaorska , Piotr Zawierucha , Danuta Ostalska-Nowicka , Michał Nowicki
• Languages of publication: EN

Abstracts

EN

Background. The mechanism of steroid resistance in children with the nephrotic syndrome is yet unknown. About 20% of patients demonstrate steroid unresponsiveness and progress to end stage renal disease. Aberrant SOCS3 and SOCS5 expression in steroid resistant and sensitive patients has previously been demonstrated. Here, we investigate genetic and epigenetic mechanisms of regulation of SOCS3 and SOCS5 transcription in nephrotic children. Methods. 76 patients with the nephrotic syndrome (40 steroid resistant and 36 steroid sensitive) and 33 matched controls were included in this study. We performed genotyping of a total of 34 single nucleotide polymorphisms for SOCS3 and SOCS5 promoters and evaluated their methylation status using MS-PCR and QMSP methods. Results. Steroid resistant patients had a significantly lower methylation of one region of SOCS3 promoter in comparison with steroid sensitive patients and controls (p < 0.0001). However, the relative methylation level in the steroid sensitive patients and controls differed significantly even before the first steroid dose (p = 0.001758). Other SOCS3 and SOCS5 promoter regions displayed no differences in methylation or were fully methylated/unmethylated in all study groups, showing site-specific methylation. The allele and genotype distribution for SOCS3 and SOCS5 markers did not differ statistically between the groups. Conclusions. We demonstrate an epigenetic mechanism of SOCS3 up-regulation in steroid resistant children with the nephrotic syndrome. The assessment of methylation/unmethylation of SOCS3 promoter might be an early marker for steroid responsiveness in NS patients.

Keywords

EN

methylation; nephrotic syndrome; single nucleotide polymorphism; steroid resistance

• Publisher: Polish Biochemical Society
• Journal: Acta Biochimica Polonica
• Year: 2016
• Volume: 63
• Issue: 1
• Pages: 131-138

Dates

published

2016

received

2015-07-09

revised

2015-11-18

accepted

2015-12-18

(unknown)

2016-02-01

Contributors

author

Katarzyna Zaorska

• Department of Histology and Embryology, Poznan University of Medical Sciences, Poznań, Poland

author

Piotr Zawierucha

• Department of Anatomy, Poznan University of Medical Sciences, Poznań, Poland

author

Danuta Ostalska-Nowicka

• Clinic of Cardiology and Nephrology, Poznan University of Medical Sciences, Poznań, Poland

author

Michał Nowicki

• Department of Histology and Embryology, Poznan University of Medical Sciences, Poznań, Poland

References

• Bagga A, Mantan M (2005) Nephrotic syndrome in children. Indian J Med Res 122: 13-28.
• Banaszak B, Banaszak P (2012) The increasing incidence of initial steroid resistance in childhood nephrotic syndrome. Pediatr Nephrol 27: 927-932.
• Bantel H, Schmitz ML, Raible A, Gregor M, Schulze-Osthoff K (2002) Critical role of NF-kappaB and stress-activated protein kinases in steroid unresponsiveness. Faseb J 16: 1832-1834.
• Barclay JL, Anderson ST, Waters JW, Curlewis JD (2007) Characterization of the SOCS3 promoter response to prostaglandin E2 in T47D cells. Mol Endocrinol 21: 2516-2528.
• Barnes PJ (1998) Anti-inflammatory actions of glucocorticoids: molecular mechanisms. Clin Sci (Lond) 94: 557-572.
• Berkley AM, Hendricks DW, Simmons KB, Fink PJ (2013) Recent thymic emigrants and mature naive T cells exhibit differential DNA methylation at key cytokine loci. J Immun 190: 6180-6186.
• Camici M (2007) The nephrotic syndrome is an immunoinflammatory disorder. Med Hypotheses 68: 900-905.
• Chaoran L (2014) MicroRNA and epigenetic controls of CD4+T cells' activation, differentiation and maintenance.
• Delcuve GP, Rastegar M, Davie JR (2009) Epigenetic control. J Cell Physiol 219: 243-250.
• Ehlting C, Haussinger D, Bode JG (2005) Sp3 is involved in the regulation of SOCS3 gene expression. Biochem J 387: 737-745.
• Fernández-Mercado M, Cebrián V, Euba B, García-Granero M, Calasanz MJ, Novo FJ, Vizmanos JL, García-Delgado M (2008) Methylation status of SOCS1 and SOCS3 in BCR-ABL negative and JAK2V617F negative chronic myeloproliferative neoplasms. Leuk Res 32: 1638-1640.
• Ghattas M, El-shaaraway F, Mesbah N, Abo-Elmatty D (2013) The methylation profile of IFN-gamma, SOCS1 and SOCS3 promoter regions in end-stage renal disease. J Data Mining Genomics Proteomics 4: 144. http://www.omicsonline.org/the-methylation-profile-of-ifn-socs-and-socs-promoter-regions-in-endstage-renal-disease-2153-0602-4-144.php?aid=19603.
• Gluckman PD, Hanson MA, Buklijas T, Low FM, Beedle AS (2009) Epigenetic mechanisms that underpin metabolic and cardiovascular diseases. Nat Rev Endocrinol 5: 401-408.
• Gómez-Guerrero C, López-Franco O, Sanjuán G, Hernández-Vargas P, Suzuki Y, Ortiz-Muñoz G, Blanco J, Egido J (2004) Suppressors of cytokine signaling regulate Fc receptor signaling and cell activation during immune renal injury. J Immunol 172: 6969-6977.
• He B, You L, Uematsu K, Matsangou M, Xu Z, He M, McCormick F, Jablons DM (2003a) Cloning and characterization of a functional promoter of the human SOCS-3 gene. Biochem Biophys Res Commun 301: 386-391.
• He B, You L, Uematsu K, Zang K, Xu Z, Lee AY, Costello JF, McCormick F, Jablons DM (2003b) SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer. Proc Natl Acad Sci 100: 14133-14138.
• Hinkes B, Vlangos C, Heeringa S, Mucha B, Gbadegesin R, Liu J, Hasselbacher K, Ozaltin F, Hildebrandt F; APN Study Group (2008) Specific podocin mutations correlate with age of onset in steroid-resistant nephrotic syndrome. J Am Soc Nephrol 19: 365-371.
• Hodge DR, Xiao W, Clausen PA, Heidecker G, Szyf M, Farrar WL (2011) Interleukin-6 regulation of the human DNA methyltransferase (HDNMT) gene in human erythroleukemia cells. J Biol Chem 276: 39508-39511.
• Holt RCL, Webb NJA (2002) Management of nephrotic syndrome in childhood. Curr Pediatr 12: 551-560.
• Huang Z, Wen Q, Zhou SF, Yu XQ (2008) Differential chemokine expression in tubular cells in response to urinary proteins from patients with nephrotic syndrome. Cytokine 42: 222-233.
• Jafar T, Agrawal S, Mahdi AA, Sharma RK, Awasthi S, Agarwal GG (2011) Cytokine gene polymorphism in idiopathic nephrotic syndrome children. Indian J Clin Biochem 26: 296-302.
• Kam JC, Szefler SJ, Surs W, Sher ER, Leung DY (1993) Combination IL-2 and IL-4 reduces glucocorticoid receptor-binding affinity and T cell response to glucocorticoids. J Immunol 151: 3460-3466.
• Kino T (2007) Tissue glucocorticoid sensitivity: beyond stochastic regulation on the diverse actions of glucocorticosteroids. Horm Metab Res 39: 420-424.
• Kobayashi Y, Aizawa A, Takizawa T, Yoshizawa C, Horiguchi H, Ikeuchi Y, Kakegawa S, Watanabe T, Maruyama K, Morikawa A, Hatada I, Arakawa H (2012) DNA methylation changes between relapse and remission of minimal change nephrotic syndrome. Pediatr Nephrol 27: 2233-2241.
• Komatsuda A, Wakui H, Iwamoto K, Harada M, Okumoto Y, Sawada K (2008) Gene expression profiling of peripheral blood mononuclear cells from patients with minimal change nephrotic syndrome by cDNA microarrays. Am J Nephrol 28: 539-547.
• Metivier R, Gallais R, Tiffoche C, Le Péron C, Jurkowska RZ, Carmouche RP, Ibberson D, Barath P, Demay F, Reid G, Benes V, Jeltsch A, Gannon F, Salbert G (2008) Cyclical DNA methylation of a transcriptionally active promoter. Nature 452: 45-50.
• Mi X, Zeng F (2008) Hypomethylation of interleukin-4 and -6 promoters in T cells from systemic lupus erythematosus patients. Acta Pharmacol Sin 29: 105-112.
• Niwa Y, Kanda H, Shikauchi Y, Saiura A, Matsubara K, Kitagawa T, Yamamoto J, Kubo T, Yoshikawa H (2005) Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and Fak signaling in human hepatocellular carcinoma. Oncogene 24: 6406-6417.
• Ostalska-Nowicka D, Śmiech M, Jaroniec M, Zaorska K, Zawierucha P, Szaflarski W, Malinska A, Nowicki M (2011) SOCS3 and SOCS5 mRNA expressions may predict initial steroid response in nephrotic syndrome children. Folia Histochem Cytobiol 49: 719-728.
• Paul C, Seiliez I, Thissen JP, Le Cam A (2000) Regulation of expression of the rat SOCS-3 gene in hepatocytes by growth hormone, interleukin-6 and glucocorticoids. Eur J Biochem 267: 5849-5857.
• Ramírez F, Fowell DJ, Puklavec M, Simmonds S, Mason D (1996) Glucocorticoids promote a Th2 cytokine response by CD4+T cells in vitro. J Immunol 156: 2406-2412.
• Richardson BC (2003) DNA methylation and autoimmune disease. Clin Immunol 109: 72-79.
• Sobti RC, Singh N, Hussain S, Suri V, Nijhawan R, Bharti AC, Bharadwaj M, Das BC (2011) Aberrant promoter methylation and loss of Suppressor of cytokine signaling-1 gene expression in the development of uterine cervical carcinogenesis. Cell Oncol Dordr 34: 533-543.
• Stenvinkel P, Karimi M, Johansson S, Axelsson J, Suliman M, Lindholm B, Heimbürger O, Barany P, Alvestrand A, Nordfors L, Qureshi AR, Ekström TJ, Schalling M (2007) Impact of inflammation on epigenetic DNA methylation - a novel risk factor for cardiovascular disease? J Intern Med 261: 488-499.
• Teitell M, Richardson B (2003) DNA methylation in the immune system. Clin Immunol 109: 2-5.
• Teodoridis JM, Strathdee G, Brown R (2004) Epigenetic silencing mediated by CpG island methylation: potential as a therapeutic target and as a biomarker. Drug Resist Updat 7: 267-278.
• Thomas DB (2009) Focal segmental glomerulosclerosis. Arch Pathol Lab Med 133: 217-223.
• Wilop S, van Gemmeren TB, Lentjes MH, van Engeland M, Herman JG, Brümmendorf TH, Jost E, Galm O (2011) Methylation-associated dysregulation of the suppressor of cytokine signaling-3 gene in multiple myeloma. Epigenetics 6: 1047-1052.
• Wilson CB, Makar KW, Shnyreva M, Fitzpatrick DR (2005) DNA methylation and the expanding epigenetics of T cell lineage commitment. Semin Immunol 17: 105-119.
• Wojdacz TK, Dobrovic A (2007) Methylation-sensitive high resolution melting (MS-HRM): a new approach for sensitive and high-throughput assessment of methylation. Nucleic Acids Res 35: e41.
• Yarwood SJ, Borland G, Sands WA, Palmer TM (2008) Identification of CCAAT/enhancer-binding proteins as exchange protein activated by cAMP-activated transcription factors that mediate the induction of the SOCS-3 gene. J Biol Chem 283: 6843-6853.
• Zhang L, Dai Y, Peng W, Lu J, Zhang Y, Wang L (2009) Genome-wide analysis of histone H3 lysine 4 trimethylation in peripheral blood mononuclear cells of minimal change nephrotic syndrome patients. AM J Nephrol 30: 505-513.
• Zhang MY, Fung TK, Chen FY, Chim CS (2013) Methylation profiling of SOCS1, SOCS2, SOCS3, CISH and SHP1 in Philadelphia-negative myeloproliferative neoplasm. J Cell Mol Med 17: 1282-1290.

Identifiers

DOI

10.18388/abp.2015_1105