20 March 2018 : Animal Research
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 Ji1ABCDEF, Honglian Wang2ACE, Zhaojun Wu3BF, Xia Zhong2BC, Menglian Zhu4D, Yuwei Zhang2B, Ruizhi Tan2D, Yuhang Liu2F, Jianchun Li2E, Li Wang2AFG*DOI: 10.12659/MSM.909236
Med Sci Monit 2018; 24: ANS1633-1641
Abstract
BACKGROUND: 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
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