Inhibition of kidney fibrosis in mice by administration of bone morphogenetic protein-7 (BMP-7)—a leading candidate for antifibrotic therapy—is associated with reversal of pathologic epigenetic modifications, according to findings from researchers at Göttingen University Medical Center, Germany, and MD Anderson Cancer Center, Houston, USA.

“Chronic kidney disease in humans and mice is invariably associated with aberrant DNA methylation—a process by which genes are turned off—and this strong correlative evidence supports a role for epigenetics in progressive kidney disease,” explains lead investigator Michael Zeisberg. Building on previous work that demonstrated promoter hypermethylation of Rasal1, which encodes RasGAP-activating-like protein 1, and subsequent silencing of Rasal1 in kidney fibrosis, the researchers investigated whether antifibrotic therapy with BMP-7 could reverse pathologic hypermethylation of Rasal1.

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In four mouse models of kidney fibrosis—unilateral ureteral obstruction, streptozotocin-induced diabetic nephropathy, Col4a3 knockout, and 5/6 nephrectomy—treatment with BMP-7, a potent antagonist of profibrotic TGF-β (a known inducer of aberrant Rasal1 methylation), inhibited kidney fibrosis and was associated with normalization of Rasal1 promoter hypermethylation. To investigate the underlying mechanism responsible for this epigenetic correction, the researchers focused on the 10–11 translocation enzymes (Tet1, Tet2, and Tet3)—known regulators of physiological demethylation. In all four fibrosis models, expression levels of Tet3, but not Tet1 or Tet2, were markedly decreased. Furthermore, this reduction could be reversed by effective BMP-7 treatment, confirming the involvement of Tet3 in BMP-7-mediated normalization of Rasal1 hypermethylation.

“The kidney has an endogenous mechanism involving Tet3 to correct its aberrant epigenome in disease settings and effective antifibrotic BMP-7 therapy in mice is indeed associated with repair of the epigenome,” states Zeisberg. “Epigenetics are a promising therapeutic target and induction of Tet3 might be a potential therapeutic approach to treat renal fibrosis,” he concludes.