| DOI: 10.29090/psa.2023.04.23.645 | Pharm Sci Asia 2023; 50(4), 371-380 |
Altenusin inhibits epithelial to mesenchymal transition via suppression of TGF-β/MAPK signaling pathway in human renal proximal tubular cells and unilateral ureteral obstruction miceNatechanok Thipboonchoo1, Sanya Sureram2, Suliporn Sa-nguansak2, Chatchai Kesornpun2, Prasat Kittakoop2,3,4, Sunhapas Soodvilai1,4,5*
1 Research Center of Transport Protein for Medical Innovation, Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand
2 Chulabhorn Research Institute, Kamphaeng Phet 6 Road, Laksi, Bangkok, Thailand
3 Chulabhorn Graduate Institute, Program in Chemical Sciences, Chulabhorn Royal Academy, Laksi, Bangkok, Thailand
4 Center of Excellence on Environmental Health and Toxicology (EHT), OPS, Ministry of Higher Education, Science, Research and Innovation, Bangkok, Thailand
5 Excellent Center for Drug Discovery, Mahidol University, Bangkok, Thailand
Renal fibrosis is recognized as a key pathological feature of chronic kidney disease (CKD), which progresses toward end stage renal disease (ESRD). Transforming growth factor (TGF)-β-induced epithelial to mesenchymal transition (EMT) of renal epithelial tubular cells is the key mechanism of renal fibrosis. The aim of this study is to investigate the pharmacological effect of altenusin, an active compound derived from fungi, on TGF-β/mitogen-activated protein kinase (MAPK) signaling pathway-induced fibrosis in renal proximal tubular cells and in mouse unilateral ureteral obstruction (UUO) model. As a result, TGF-β1 induced EMT of RPTECT/TERT1 cells (an immortalized human renal proximal tubular cells) by concentration- and time-dependent manners. Incubating cells with 10 ng/ml TGF-β1 for 48 hours significantly upregulated MAPK signaling pathway by increase phosphorylated (p)-Jun N-terminal kinase (JNK), p-p38, and p-Extracellular signal-regulated kinase (ERK) 1/2. Treating the cells with altenusin (50 -100 μM) significantly attenuated TGF-β1-induced EMT. The inhibitory effect of altenusin on EMT was mediated by inhibition of p38 and ERK1/2 but not JNK. UUO in mice for 14 days dramatically increased p-JNK, p-p38, and p-ERK1/2, activation of these proteins by UUO were attenuated by co-treatment with altenusin 3 mg/kg. These results demonstrate the inhibitory effect of altenusin on TGF-β/MAPK signaling pathway-induced EMT in human renal proximal tubular cells and in animal model of renal fibrosis.
Keyword:
Altenusin, Epithelial to mesenchymal transition, Transforming growth factor ?, MAPK, Unilateral ureteral obstruction
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