title: DNA hypermethylation in hyperhomocysteinemia contributes to abnormal extracellular matrix metabolism in the kidney.
abstract: 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-β-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.
authors.affiliation: Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, Kentucky, USA sbpush01@louisville.edu u0sen001@louisville.edu.
authors.forename: Sathnur
authors.initials: S
authors.lastname: Pushpakumar
authors.affiliation: Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, Kentucky, USA.
authors.forename: Sourav
authors.initials: S
authors.lastname: Kundu
authors.affiliation: Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, Kentucky, USA.
authors.forename: Nithya
authors.initials: N
authors.lastname: Narayanan
authors.affiliation: Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, Kentucky, USA sbpush01@louisville.edu u0sen001@louisville.edu.
authors.forename: Utpal
authors.initials: U
authors.lastname: Sen
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000378:metabolism; D003568:Cytidine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D004248:DNA (Cytosine-5-)-Methyltransferases; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D037502:Galectin 3 / Q000235:genetics / Q000378:metabolism; D020138:Hyperhomocysteinemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D037502:Galectin 3; C485095:Lgals3 protein, mouse; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; C012201:5'-azacytidine 5'-monophosphate; D003094:Collagen; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D003541:Cystathionine beta-Synthase; D003568:Cytidine Monophosphate
keywords: 5-aza-2′-deoxycytidine; epigenetics; matrix metalloproteinase; renal fibrosis