Specific Inhibitor of Smad3 (SIS3) Attenuates Fibrosis, Apoptosis, and Inflammation in Unilateral Ureteral Obstruction Kidneys by Inhibition of Transforming Growth Factor β (TGF-β)/Smad3 Signaling.

Content Provider	Europe PMC
Author	Ji, Xingli Wang, Honglian Wu, Zhaojun Zhong, Xia Zhu, Menglian Zhang, Yuwei Tan, Ruizhi Liu, Yuhang Li, Jianchun Wang, Li
Copyright Year	2018
Abstract	BackgroundFibrosis is the common pathological feature in most kinds of chronic kidney disease (CKD). TGF-β/Smads signaling is the master pathway regulating kidney fibrosis pathogenesis, in which Smad3 acts as the integrator of various pro-fibrosis signals. In this study, we analyzed the role of SIS3, a specific inhibitor of Smad3, in mouse unilateral ureteral obstruction (UUO) kidneys.Material/MethodsUUO mice were intraperitoneally injected with 0.2 mg/kg/day or 2 mg/kg/day of SIS3 or control saline for 7 days, followed by analysis of structure injury, fibrosis status, inflammation, apoptosis, and TGF-β/Smads signaling activity.ResultsOur results indicated that SIS3 treatment dosage-dependently relieved the gross structure injury and tubular necrosis in UUO kidneys. Masson staining, immunohistochemistry, and real-time PCR showed significantly decreased extracellular matrix deposition, fibronectin staining intensity, and RNA levels of collagen I and collagen III in SIS3-treated UUO kidneys. SIS3 treatment also suppressed the activation of myofibroblasts, as evidenced by decreased expression levels of α-SMA and vimentin in UUO kidneys. The TGF-β/Smads signaling activity analysis showed that SIS3 inhibited the phosphorylation of Smad3 but not Smad2 and decreased the protein level of TGF-β1, suggesting specific inhibition of the TGF-β/Smad3 pathway in UUO kidneys. Furthermore, SIS3 treatment also ameliorated the increased pro-inflammatory TNF-α and COX2 in UUO kidneys and circulating IL-1β in UUO mice, and inhibited caspase-3 activity and the number of apoptotic cells.ConclusionsSIS3 ameliorated fibrosis, apoptosis, and inflammation through inhibition of TGF-β/Smad3 signaling in UUO mouse kidneys.
ISSN	12341010
Journal	Medical Science Monitor : International Medical Journal of Experimental and Clinical Research
Volume Number	24
PubMed Central reference number	PMC5872904
PubMed reference number	29555895
e-ISSN	16433750
DOI	10.12659/msm.909236
Language	English
Publisher	International Scientific Literature, Inc.
Publisher Date	2018-03-20
Access Restriction	Open
Rights License	This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) © Med Sci Monit, 2018
Subject Keyword	Fibrosis Inflammation Transforming Growth Factor beta Apoptosis
Content Type	Text
Resource Type	Article
Subject	Medicine