title: DNA methylation in Cosmc promoter region and aberrantly glycosylated IgA1 associated with pediatric IgA nephropathy.
abstract: IgA nephropathy (IgAN) is one of the most common glomerular diseases leading to end-stage renal failure. Elevation of aberrantly glycosylated IgA1 is a key feature of it. The expression of the specific molecular chaperone of core1ß1, 3galactosyl transferase (Cosmc) is known to be reduced in IgAN. We aimed to investigate whether the methylation of CpG islands of Cosmc gene promoter region could act as a possible mechanism responsible for down-regulation of Cosmc and related higher secretion of aberrantly glycosylated IgA1in lymphocytes from children with IgA nephropathy. Three groups were included: IgAN children (n = 26), other renal diseases (n = 11) and healthy children (n = 13). B-lymphocytes were isolated and cultured, treated or not with IL-4 or 5-Aza-2'-deoxycytidine (AZA). The levels of DNA methylation of Cosmc promotor region were not significantly different between the lymphocytes of the three children populations (P = 0.113), but there were significant differences between IgAN lymphocytes and lymphocytes of the other two children populations after IL-4 (P<0.0001) or AZA (P<0.0001). Cosmc mRNA expression was low in IgAN lymphocytes compared to the other two groups (P<0.0001). The level of aberrantly glycosylated IgA1 was markedly higher in IgAN group compared to the other groups (P<0.0001). After treatment with IL-4, the levels of Cosmc DNA methylation and aberrantly glycosylated IgA1 in IgAN lymphocytes were remarkably higher than the other two groups (P<0.0001) with more markedly decreased Cosmc mRNA content (P<0.0001). After treatment with AZA, the levels in IgAN lymphocytes were decreased, but was still remarkably higher than the other two groups (P<0.0001), while Cosmc mRNA content in IgAN lymphocytes were more markedly increased than the other two groups (P<0.0001). The alteration of DNA methylation by IL-4 or AZA specifically correlates in IgAN lymphocytes with alterations in Cosmc mRNA expression and with the level of aberrantly glycosylated IgA1 (r = -0.948, r = 0. 707). Our results suggested that hypermethylation of Cosmc promoter region could be a key mechanism for the reduction of Cosmc mRNA expression in IgAN lymphocytes with associated increase in aberrantly glycosylated IgA1.
authors: Department of nephrology, Beijing Children's Hospital, Capital Medical University, Beijing, China.
authors: Qiang
authors: Q
authors: Sun
authors: Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
authors: Jianqian
authors: J
authors: Zhang
authors: Department of nephrology, Beijing Children's Hospital, Capital Medical University, Beijing, China.
authors: Nan
authors: N
authors: Zhou
authors: Department of nephrology, Beijing Children's Hospital, Capital Medical University, Beijing, China.
authors: Xiaorong
authors: X
authors: Liu
authors: Department of nephrology, Beijing Children's Hospital, Capital Medical University, Beijing, China.
authors: Ying
authors: Y
authors: Shen
mesh_terms: D000293:Adolescent; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005922:Glomerulonephritis, IGA / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D007070:Immunoglobulin A / Q000378:metabolism*; D015847:Interleukin-4 / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D018832:Molecular Chaperones / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: C505369:C1GALT1C1 protein, human; D007070:Immunoglobulin A; D018832:Molecular Chaperones; D012333:RNA, Messenger; D015847:Interleukin-4; D000077209:Decitabine; D001374:Azacitidine
references: Kidney Blood Press Res. 2008;31(1):29-37
references: 18182777
references: Nephrol Dial Transplant. 2008 May;23(5):1608-14
references: 18202089
references: Kidney Int. 2008 May;73(10):1128-36
references: 18322546
references: Clin Exp Nephrol. 2008 Oct;12(5):332-8
references: 18404247
references: Nephrol Dial Transplant. 2009 Jan;24(1):321-4
references: 18840896
references: Kidney Int. 2009 Mar;75(5):536-41
references: 19037255
references: Kidney Int. 2009 Sep;76(5):546-56
references: 19571790
references: Kidney Int. 2009 Sep;76(5):534-45
references: 19571791
references: Nephrol Dial Transplant. 2010 Dec;25(12):3890-7
references: 20551088
references: Clin Dev Immunol. 2011;2011:470803
references: 21318178
references: Nephrol Dial Transplant. 2011 Aug;26(8):2533-6
references: 21273233
references: Sichuan Da Xue Xue Bao Yi Xue Ban. 2011 Nov;42(6):762-5
references: 22332537
references: J Am Soc Nephrol. 2012 May;23(5):814-24
references: 22362909
references: J Biol Chem. 2012 May 4;287(19):15317-29
references: 22416136
references: Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16613-8
references: 12464682
references: Am J Kidney Dis. 2000 Aug;36(2):227-37
references: 10922300
references: J Clin Invest. 2008 Feb;118(2):629-39
references: 18172551
references: J Biol Chem. 2012 Nov 30;287(49):41523-33
references: 23035125
references: Int Urol Nephrol. 2013 Apr;45(2):571-9
references: 23136028
references: Am J Nephrol. 2013;38(4):321-32
references: 24107646
references: J Biol Chem. 2014 Feb 21;289(8):5330-9
references: 24398680
references: Discov Med. 2014 Mar;17(93):131-8
references: 24641955
references: PLoS One. 2014;9(3):e91756
references: 24658533
references: PLoS One. 2014;9(5):e96779
references: 24804776
references: Biol Trace Elem Res. 2014 Jun;159(1-3):69-80
references: 24811888
references: Epigenetics. 2014 Jun;9(6):896-909
references: 24699858
references: Biochim Biophys Acta. 1999 Oct 8;1455(2-3):255-68
references: 10571017
references: Science. 1984 Jun 15;224(4654):1198-206
references: 6729450