Hypermethylation of RASAL1: A Key for Renal Fibrosis

Chronic kidney disease is a global epidemic that affects estimated 10% of the world population. As the final common pathway of chronic kidney diseases, renal fibrosis can result in massive destruction of normal kidney structure and subsequent impairment of the function. Activated fibroblasts are recognized to be principal mediators of renal fibrosis. Unlike in physiological wound repair, where fibroblast activation is spontaneously reversible, the fibroblast activation associated with renal fibrosis is perpetuated, and fibroblastsmaintain their activated phenotype even when cultured in vitro (Müller and Rodemann, 1991; Rodemann and Müller, 1991). Epigeneticmodifications can cause the perpetuation of renalfibrosis. Previous studies have showed a prominent role of Ras signaling pathway in renal fibrosis (Hendry and Sharpe, 2003). Hypermethylation of RASAL1, encoding an inhibitor of the Ras protein, is associated with the perpetuation of fibroblast activation and experimental renal fibrosis (Bechtel et al., 2010). Transcriptional RASAL1 repression is associated with fibroblast activation in both physiological kidney repair and pathological kidney fibrosis. In physiological kidney repair, reversible fibroblast activation is associated with reversible RASAL1 suppression without RASAL1 hypermethylation; whereas in pathological kidney fibrosis, perpetual fibroblast activation is associated with irreversible RASAL1 expression due to RASAL1 promoter hypermethylation (Bechtel et al., 2010). Furthermore, this hypermethylation can be induced by long-term exposure to proinflammatory cytokines such as TGF-β1 (Bechtel et al., 2010). Bone morphogenic protein 7, an inhibitor of TGF-β1 signaling, normalizes the RASAL promoter hypermethylation and successfully inhibits experimental kidney fibrosis (Tampe et al., 2014). In their article published in this issue of EBioMedicine, Tampe et al. demonstrated that the de-methylation of RASAL1 promoter induced by hydralazine is associated with ameliorating effects of experimental renal fibrosis. At the mechanistic level they demonstrated that hydralazine erases the aberrant RASAL1 promotermethylationmark and ameliorates experimental fibrogenesis by inducing a physiological mechanism of Tet3-mediated hydroxymethylation and subsequent replacement with unmethylated CpGs. The results add new information to our current knowledge. First, by using transgenic mice harboring transgenes for doxycycline-inducible RASAL1 overexpression, RASAL1 over-expression was demonstrated