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

Hisato Shima, Kensuke Sasaki, Takehiro Suzuki, Chikahisa Mukawa, Ten Obara, Yuki Oba, Akihiro Matsuo, Takayasu Kobayashi, Eikan Mishima, Shun Watanabe, Yasutoshi Akiyama, Koichi Kikuchi, Tetsuro Matsuhashi, Yoshitsugu Oikawa, Fumika Nanto, Yukako Akiyama, Hsin Jung Ho, Chitose Suzuki, Daisuke Saigusa, Atsushi MasamuneYoshihisa Tomioka, Takao Masaki, Sadayoshi Ito, Ken Ichiro Hayashi, Takaaki Abe

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Abstract

Renal 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.

Original languageEnglish
Article number1884
JournalScientific reports
Volume7
Issue number1
DOIs
Publication statusPublished - 2017 Dec 1

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    Shima, H., Sasaki, K., Suzuki, T., Mukawa, C., Obara, T., Oba, Y., Matsuo, A., Kobayashi, T., Mishima, E., Watanabe, S., Akiyama, Y., Kikuchi, K., Matsuhashi, T., Oikawa, Y., Nanto, F., Akiyama, Y., Ho, H. J., Suzuki, C., Saigusa, D., ... Abe, T. (2017). A novel indole compound MA-35 attenuates renal fibrosis by inhibiting both TNF-α and TGF-β1 pathways. Scientific reports, 7(1), [1884]. https://doi.org/10.1038/s41598-017-01702-7