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

Scientific Reports
Hisato ShimaTakaaki Abe

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 pr...Continue Reading

References

Mar 30, 1984·Journal of Immunological Methods·D A Flick, G E Gifford
Feb 13, 2001·Kidney International·C Guijarro, J Egido
Oct 10, 2002·American Journal of Physiology. Renal Physiology·Saulo Klahr, Jeremiah Morrissey
Sep 6, 2003·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Shigehiko ImagawaMasayuki Yamamoto
Dec 16, 2006·American Journal of Physiology. Regulatory, Integrative and Comparative Physiology·K K MeldrumD R Meldrum
Oct 31, 2007·Autoimmunity Reviews·G ValesiniM Di Franco
Jun 3, 2011·European Respiratory Review : an Official Journal of the European Respiratory Society·C J SchaeferK Kossen
Aug 29, 2012·Laboratory Investigation; a Journal of Technical Methods and Pathology·Kazunori InoueHiromi Rakugi
Nov 2, 2012·Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association·Motoko Yanagita
Jun 8, 2013·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Nagendra Kumar KaushikEun Ha Choi
Mar 13, 2014·The American Journal of Pathology·Takanori KomadaMasafumi Takahashi
Nov 2, 2014·The Journal of Pharmacology and Experimental Therapeutics·Hong-Wei Yao, Jun Li
Mar 19, 2015·The New England Journal of Medicine·Don C RockeyJoseph A Hill
Jun 6, 2015·Journal of the American Society of Nephrology : JASN·Kensuke SasakiTakao Masaki
Aug 8, 2015·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Tomoko FujitaShuh Narumiya
Nov 27, 2015·Journal of the American Society of Nephrology : JASN·Takehiro SuzukiTakaaki Abe
Apr 26, 2016·Nature Reviews. Nephrology·Xiao-Ming MengHui Yao Lan

❮ Previous
Next ❯

Citations

Mar 23, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Lingyu LiZhongmei Zou
Apr 25, 2019·Nature Communications·Koichi KikuchiTakaaki Abe
Nov 27, 2019·Journal of the American Society of Nephrology : JASN·Eikan MishimaTakaaki Abe
Mar 19, 2019·Oxidative Medicine and Cellular Longevity·Shashank ShrishrimalRebecca E Oberley-Deegan
Jan 1, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Xiangju SunYuhua Fan

❮ Previous
Next ❯

Methods Mentioned

BETA
PCR
ChIP
immunoprecipitation
ELISA
Assay

Software Mentioned

Image J
JMP

Related Concepts

Related Feeds

Cell Signaling & Cancer Epigenetics (Keystone)

Epigenetic changes are present and dysregulated in many cancers, including DNA methylation, non-coding RNA segments and post-translational protein modifications. This feed covers the latest research on signaling and epigenetics in cell growth and cancer.