Induction of inactive TGF-β1 monomer formation by hydrogen sulfide contributes to its suppressive effects on Ang II- and TGF-β1-induced EMT in renal tubular epithelial cells
- Divison of Molecular Signaling, Department of the Advanced Biomedical Research, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi (Japan)
- Department of Immunology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi (Japan)
- Department of Urology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi (Japan)
Highlights: • H{sub 2}S has anti-fibrotic actions with little information available about its mechanisms. • Ang II induced EMT in renal tubular epithelial cells via TGF-β. • H{sub 2}S inhibited Ang II- and TGF-β-induced EMT. • H{sub 2}S suppressed Ang II-induced activation of TGF-β. • H{sub 2}S inactivated TGF-β via cleavage of the disulfide bonds. Hydrogen sulfide (H{sub 2}S), an endogenous gas mediator with multifaced biological functions, has been shown to be effective in the prevention and treatment of renal sclerosis in several models of chronic renal diseases. The mechanisms involved are still unclear. Given that Ang II- and TGF-β-induced renal tubular epithelial-mesenchymal transition (EMT) is a pivotal cellular event leading to renal sclerosis, we examined whether and how H{sub 2}S intervened the processes of EMT. Ang II stimulated EMT in renal tubular epithelial cells, as indicated by the increased level of α-smooth muscle actin and a decreased level of E-cadherin. This effect of Ang II was blocked by a TGF-β receptor kinase inhibitor, indicative of a mediating role of TGF-β. Consistently, Ang II stimulated TGF-β activation and addition of the exogenous TGF-β1 also induced EMT. In the presence of H{sub 2}S donor NaHS, the EMT-promoting actions of Ang II and TGF-β1 were abolished, which was associated with a reduced TGF-β activity. Further analysis using a human recombinant active TGF-β1 revealed that H{sub 2}S cleaved the disulfide bond in the dimeric active TGF-β1 and promoted the formation of inactive TGF-β1 monomer. Collectively, these results indicate that H{sub 2}S counteracted Ang II- and TGF-β1-induced EMT through mechanisms involving direct inactivation of TGF-β1. Our study thus provides novel mechanistic insight into the anti-fibrotic actions of H{sub 2}S and suggest that H{sub 2}S could be used to treat renal sclerotic diseases.
- OSTI ID:
- 23137047
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 501, Issue 2; Other Information: Copyright (c) 2018 Elsevier Inc. All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
Similar Records
Protective effect of Ac-SDKP on alveolar epithelial cells through inhibition of EMT via TGF-β1/ROCK1 pathway in silicosis in rat
Celecoxib offsets the negative renal influences of cyclosporine via modulation of the TGF-β1/IL-2/COX-2/endothelin ET{sub B} receptor cascade