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

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.

Gut microbiome-derived phenyl sulfate contributes to albuminuria in diabetic kidney disease

“…The preserved tubular area was also quantified by measurement at ×20 magnification in the whole renal cortex area in the field using Image J. The fibrotic area was quantified by measurement at ×200 magnification in 20 random nonoverlapping fields using Image J 61 . Electron microscopic analysis was performed as previously reported 17 .…”

Reactive Oxygen Species Drive Epigenetic Changes in Radiation-Induced Fibrosis

“…Inhibition of HMTs, using 3-deazaneplanocin A (DZNep), suppressed the progression of renal and pulmonary fibrosis [242, 243]. Further, inhibition of the TGF- β and TNF- α signaling pathways using a novel indole compound, MA-35, resulted in the attenuation of renal inflammation and fibrosis by decreasing H3K4me1 histone modification at the COL1A1 and PAI-1 fibrotic gene promoters [244]. Inhibition of H3K9me1 using BIX01294, an inhibitor of G9a methyltransferase, prevented the development of renal fibrosis by maintaining expression of the antifibrotic gene, Klotho [232].…”

Angiotensin-converting enzyme inhibitor reduces scar formation by inhibiting both canonical and noncanonical TGF-β1 pathways

“…The transforming growth factor-β (TGF-β) superfamily regulates many cellular functions, including cell growth, differentiation, adhesion, migration, and apoptosis 18 . Abnormal TGF-β signaling has been detected in increasing numbers of fibrotic and inflammatory conditions, including liver cirrhosis, renal fibrosis, systemic sclerosis, and hypertrophic scars 2 , 19 – 22 . TGF-β1 occurs almost ubiquitously in mammalian tissues, and the development of tissue fibrosis is primarily attributed to this protein 23 .…”