PMID- 26224753
OWN - NLM
STAT- MEDLINE
DCOM- 20160211
LR  - 20211203
IS  - 1530-6860 (Electronic)
IS  - 0892-6638 (Print)
IS  - 0892-6638 (Linking)
VI  - 29
IP  - 11
DP  - 2015 Nov
TI  - DNA hypermethylation in hyperhomocysteinemia contributes to abnormal 
      extracellular matrix metabolism in the kidney.
PG  - 4713-25
LID - 10.1096/fj.15-272443 [doi]
AB  - Hyperhomocysteinemia (HHcy) is prevalent in patients with chronic kidney disease 
      (CKD) and end-stage renal disease (ESRD). Emerging studies suggest that 
      epigenetic mechanisms contribute to the development and progression of fibrosis 
      in CKD. HHcy and its intermediates are known to alter the DNA methylation 
      pattern, which is a critical regulator of epigenetic information. In this study, 
      we hypothesized that HHcy causes renovascular remodeling by DNA hypermethylation, 
      leading to glomerulosclerosis. We also evaluated whether the DNA methylation 
      inhibitor, 5-aza-2'-deoxycytidine (5-Aza) could modulate extracellular matrix 
      (ECM) metabolism and reduce renovascular fibrosis. C57BL/6J (wild-type) and 
      cystathionine-beta-synthase (CBS(+/-)) mice, treated without or with 5-Aza (0.5 
      mg/kg body weight, i.p.), were used. CBS(+/-) mice showed high plasma Hcy levels, 
      hypertension, and significant glomerular and arteriolar injury. 5-Aza treatment 
      normalized blood pressure and reversed renal injury. CBS(+/-) mice showed global 
      hypermethylation and up-regulation of DNA methyltransferase-1 and -3a. 
      Methylation-specific PCR showed an imbalance between matrix metalloproteinase 
      (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)-1 and -2 and also 
      increased collagen and galectin-3 expression. 5-Aza reduced abnormal DNA 
      methylation and restored the MMP-9/TIMP-1, -2 balance. In conclusion, our data 
      suggest that during HHcy, abnormal DNA methylation and an imbalance between MMP-9 
      and TIMP-1 and -2 lead to ECM remodeling and renal fibrosis.
CI  - (c) FASEB.
FAU - Pushpakumar, Sathnur
AU  - Pushpakumar S
AD  - Department of Physiology and Biophysics, University of Louisville School of 
      Medicine, Louisville, Kentucky, USA sbpush01@louisville.edu 
      u0sen001@louisville.edu.
FAU - Kundu, Sourav
AU  - Kundu S
AD  - Department of Physiology and Biophysics, University of Louisville School of 
      Medicine, Louisville, Kentucky, USA.
FAU - Narayanan, Nithya
AU  - Narayanan N
AD  - Department of Physiology and Biophysics, University of Louisville School of 
      Medicine, Louisville, Kentucky, USA.
FAU - Sen, Utpal
AU  - Sen U
AD  - Department of Physiology and Biophysics, University of Louisville School of 
      Medicine, Louisville, Kentucky, USA sbpush01@louisville.edu 
      u0sen001@louisville.edu.
LA  - eng
GR  - R01 HL104103/HL/NHLBI NIH HHS/United States
GR  - HL-104103/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150729
PL  - United States
TA  - FASEB J
JT  - FASEB journal : official publication of the Federation of American Societies for 
      Experimental Biology
JID - 8804484
RN  - 0 (Galectin 3)
RN  - 0 (Lgals3 protein, mouse)
RN  - 0 (Timp1 protein, mouse)
RN  - 0 (Tissue Inhibitor of Metalloproteinase-1)
RN  - 127497-59-0 (Tissue Inhibitor of Metalloproteinase-2)
RN  - 2226-72-4 (5'-azacytidine 5'-monophosphate)
RN  - 9007-34-5 (Collagen)
RN  - EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferases)
RN  - EC 2.1.1.37 (DNA Methyltransferase 3A)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
RN  - EC 3.4.24.35 (Mmp9 protein, mouse)
RN  - EC 4.2.1.22 (Cystathionine beta-Synthase)
RN  - F469818O25 (Cytidine Monophosphate)
SB  - IM
MH  - Acute Kidney Injury/drug therapy/genetics/*metabolism/pathology
MH  - Animals
MH  - Blood Pressure/drug effects
MH  - Collagen/genetics/metabolism
MH  - Cystathionine beta-Synthase/genetics/metabolism
MH  - Cytidine Monophosphate/analogs & derivatives/pharmacology
MH  - DNA (Cytosine-5-)-Methyltransferases
MH  - *DNA Methylation
MH  - DNA Methyltransferase 3A
MH  - Extracellular Matrix/genetics/*metabolism/pathology
MH  - Fibrosis
MH  - Galectin 3/genetics/metabolism
MH  - Hyperhomocysteinemia/drug therapy/genetics/*metabolism/pathology
MH  - Kidney/*metabolism/pathology
MH  - Matrix Metalloproteinase 9/genetics/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Tissue Inhibitor of Metalloproteinase-1/genetics/metabolism
MH  - Tissue Inhibitor of Metalloproteinase-2/genetics/metabolism
PMC - PMC4608914
OTO - NOTNLM
OT  - 5-aza-2'-deoxycytidine
OT  - epigenetics
OT  - matrix metalloproteinase
OT  - renal fibrosis
EDAT- 2015/08/01 06:00
MHDA- 2016/02/13 06:00
PMCR- 2016/11/01
CRDT- 2015/07/31 06:00
PHST- 2015/04/13 00:00 [received]
PHST- 2015/07/20 00:00 [accepted]
PHST- 2015/07/31 06:00 [entrez]
PHST- 2015/08/01 06:00 [pubmed]
PHST- 2016/02/13 06:00 [medline]
PHST- 2016/11/01 00:00 [pmc-release]
AID - fj.15-272443 [pii]
AID - FJ_272443 [pii]
AID - 10.1096/fj.15-272443 [doi]
PST - ppublish
SO  - FASEB J. 2015 Nov;29(11):4713-25. doi: 10.1096/fj.15-272443. Epub 2015 Jul 29.