Hypermethylation of RASAL1: A Key for Renal Fibrosis

Methylation of CpG island promoters is an epigenetic event that can effectively silence transcription over multiple cell generations. Hypermethylation of the Rasal1 promoter contributes to activation of fibroblasts and progression of kidney fibrosis. Here, we explored whether such causative hypermethylation could be reversed through endogenous mechanisms and whether such reversal of hypermethylation is a constituent of the antifibrotic activity of bone morphogenic protein 7 (BMP7). We show that successful inhibition of experimental kidney fibrosis through administration of BMP7 associates with normalization of Rasal1 promoter hypermethylation. Furthermore, this reversal of pathologic hypermethylation was achieved specifically through Tet3-mediated hydroxymethylation. Collectively, our findings reveal a new mechanism that may be exploited to facilitate therapeutic DNA demethylation to reverse kidney fibrosis. Copyright © 2014 by the American Society of Nephrology.

Fibroblast cultures from normal human kidneys (NKF cells) and kidneys affected with interstitial fibrosis (FKIF cells) were analyzed for in vitro growth, differentiation dynamics, and collagen synthesis. FKIF cells are characterized by hyperproliferative growth, resulting in a prolonged mitotic lifespan, by an altered differentiation pattern, and by the expression of the FKIF cell-specific protein "fibrosin" (molecular weight 53 kd, isoelectric point [pi] 6.1). Furthermore, FKIF cells synthesize four to five times more total collagen per cell as compared with NKF cells, and the relative amounts of the collagen types produced (type I, III, and V) are significantly different from controls. Thus, the in vitro cell system of FKIF cells may help to elucidate the underlying mechanisms triggering the induction and progression of renal interstitial fibrosis in vivo.

Epigenetics is a new development in complex non-Mendelian disease, which may not only uncover etiologic and pathogenic mechanisms but may also provide the basis for the development of medications that would target the primary epigenetic causes of such diseases. Such epigenetic drugs would be novel, potentially possessing substantially higher therapeutic potential and a much lower rate of adverse effects in comparison to current symptomatic treatments. A collection of epigenetic drugs already exist at various stages of development and, although their effectiveness has yet to be maximized, they show great promise in the treatment of cancer, psychiatric disorders, and other complex diseases. Here we present a review of the epigenetic theory of complex disease and an evaluation of current epigenetic therapies, as well as predictions of the future directions in this expanding field.