DNA hypermethylation in hyperhomocysteinemia contributes to abnormal extracellular matrix metabolism in the kidney

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 hyper...