A novel indole compound MA-35 attenuates renal fibrosis by inhibiting both TNF-α and TGF-β 1 pathways

• Published in: Scientific reports 2017-05, Vol.7 (1), p.1884
• Main Authors: Shima, Hisato, Sasaki, Kensuke, Suzuki, Takehiro, Mukawa, Chikahisa, Obara, Ten, Oba, Yuki, Matsuo, Akihiro, Kobayashi, Takayasu, Mishima, Eikan, Watanabe, Shun, Akiyama, Yasutoshi, Kikuchi, Koichi, Matsuhashi, Tetsuro, Oikawa, Yoshitsugu, Nanto, Fumika, Akiyama, Yukako, Ho, Hsin-Jung, Suzuki, Chitose, Saigusa, Daisuke, Masamune, Atsushi, Tomioka, Yoshihisa, Masaki, Takao, Ito, Sadayoshi, Hayashi, Ken-Ichiro, Abe, Takaaki
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Disease Models, Animal; Extracellular Matrix - metabolism; Fibrosis; Hepatitis - drug therapy; Hepatitis - etiology; Hepatitis - metabolism; Hepatitis - pathology; Histones - metabolism; Humans; I-kappa B Kinase - metabolism; Indoles - pharmacology; Kidney Diseases - drug therapy; Kidney Diseases - etiology; Kidney Diseases - metabolism; Kidney Diseases - pathology; Lipopolysaccharides - adverse effects; Male; Methylation; Mice; Models, Biological; Phosphorylation - drug effects; Signal Transduction - drug effects; Smad3 Protein - metabolism; Transforming Growth Factor beta1 - metabolism; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 2045-2322
• DOI: 10.1038/s41598-017-01702-7

Renal fibrosis is closely related to chronic inflammation and is under the control of epigenetic regulations. Because the signaling of transforming growth factor-β (TGF-β ) and tumor necrosis factor-α (TNF-α) play key roles in progression of renal fibrosis, dual blockade of TGF-β 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-β effect by inhibiting Smad3 phosphorylation, resulting in the downregulation of TGF-β -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-β -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.