Shima, HisatoSasaki, KensukeSuzuki, TakehiroMukawa, ChikahisaObara, TenOba, YukiMatsuo, AkihiroKobayashi, TakayasuMishima, EikanWatanabe, ShunAkiyama, YasutoshiKikuchi, KoichiMatsuhashi, TetsuroOikawa, YoshitsuguNanto, FumikaAkiyama, YukakoHo, Hsin-JungSuzuki, ChitoseSaigusa, DaisukeMasamune, AtsushiTomioka, YoshihisaMasaki, TakaoIto, SadayoshiHayashi, Ken-ichiroAbe, Takaaki2017-08-242017-08-242017-05-15Shima, H., Sasaki, K., Suzuki, T., Mukawa, C., Obara, T., Oba, Y., … Abe, T. (2017). A novel indole compound MA-35 attenuates renal fibrosis by inhibiting both TNF-α and TGF-β1 pathways. Scientific Reports, 7, 1884. http://doi.org/10.1038/s41598-017-01702-7https://hdl.handle.net/1805/13917Renal fibrosis is closely related to chronic inflammation and is under the control of epigenetic regulations. Because the signaling of transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α (TNF-α) play key roles in progression of renal fibrosis, dual blockade of TGF-β1 and TNF-α is desired as its therapeutic approach. Here we screened small molecules showing anti-TNF-α activity in the compound library of indole derivatives. 11 out of 41 indole derivatives inhibited the TNF-α effect. Among them, Mitochonic Acid 35 (MA-35), 5-(3, 5-dimethoxybenzyloxy)-3-indoleacetic acid, showed the potent effect. The anti-TNF-α activity was mediated by inhibiting IκB kinase phosphorylation, which attenuated the LPS/GaIN-induced hepatic inflammation in the mice. Additionally, MA-35 concurrently showed an anti-TGF-β1 effect by inhibiting Smad3 phosphorylation, resulting in the downregulation of TGF-β1-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-β1-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.en-USAttribution-NonCommercial-NoDerivs 3.0 United StatesRenal fibrosisChronic inflammationEpigenetic regulationstransforming growth factor-β1 (TGF-β1)Tumor necrosis factor-α (TNF-α)Article