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
Xingli Ji, Honglian Wang, Zhaojun Wu, Xia Zhong, Menglian Zhu, Yuwei Zhang, Ruizhi Tan, Yuhang Liu, Jianchun Li, Li Wang
College of Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan, China (mainland)
Med Sci Monit 2018; 24: ANS1633-1641
Available online: 2018-03-20
Fibrosis 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 AND METHODS: UUO 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.
RESULTS: Our 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 a-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.
CONCLUSIONS: SIS3 ameliorated fibrosis, apoptosis, and inflammation through inhibition of TGF-b/Smad3 signaling in UUO mouse kidneys.
Keywords: Fibrosis, Transforming Growth Factor beta