A novel indole compound MA-35 attenuates renal fibrosis by inhibiting both TNF-α and TGF-β1 pathways

Renal fibrosis is closely related to chronic inflammation and is under the control of epigenetic regulations. Because the signaling of transforming growth factor-beta 1 (TGF-beta(1)) and tumor necrosis factor-alpha (TNF-alpha) play key roles in progression of renal fibrosis, dual blockade of TGF-beta(1) and TNF-alpha is desired as its therapeutic approach. Here we screened small molecules showing anti-TNF-alpha activity in the compound library of indole derivatives. 11 out of 41 indole derivatives inhibited the TNF-alpha effect. Among them, Mitochonic Acid 35 (MA-35), 5-(3, 5-dimethoxybenzyloxy)-3-indoleacetic acid, showed the potent effect. The anti-TNF-alpha activity was mediated by inhibiting I kappa B kinase phosphorylation, which attenuated the LPS/GaIN-induced hepatic inflammation in the mice. Additionally, MA-35 concurrently showed an anti-TGF-beta(1) effect by inhibiting Smad3 phosphorylation, resulting in the downregulation of TGF-beta(1)-induced fibrotic gene expression. In unilateral ureter obstructed mouse kidney, which is a renal fibrosis model, MA-35 attenuated renal inflammation and fibrosis with the downregulation of inflammatory cytokines and fibrotic gene expressions. Furthermore, MA-35 inhibited TGF-beta(1)-induced H3K4me1 histone modification of the fibrotic gene promoter, leading to a decrease in the fibrotic gene expression. MA-35 affects multiple signaling pathways involved in the fibrosis and may recover epigenetic modification; therefore, it could possibly be a novel therapeutic drug for fibrosis.