DNA hypermethylation in hyperhomocysteinemia contributes to abnormal extracellular matrix metabolism in the kidney. Issue 11 (29th July 2015)

• Record Type: Journal Article
• Authors: Pushpakumar, Sathnur; Kundu, Sourav; Narayanan, Nithya; Sen, Utpal
• Is Part Of: FASEB journal. Volume 29:Issue 11(2015)
• Page Start: 4713
• Page End: 4725
• Publication Date: 2015-07-29
• Subjects: epigenetics -- renal fibrosis -- 5‐aza‐2'‐deoxycytidine -- matrix metalloproteinase; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.15-272443
• Languages: English
• ISSNs: 0892-6638

Abstract

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.—Pushpakumar, S., Kundu, S., Narayanan, N., Sen, U. DNA hypermethylation in hyperhomocysteinemia contributes to abnormal extracellular matrix metabolism in the kidney. FASEB J. 29, 4713‐4725 (2015). www.fasebj.org