Protective effects of STAT3 inhibitor S3I-201 in experimental renal tubulointerstitial fibrosis

Objective To investigate the protective effects of STAT3 inhibitor S3I-201 in experimental renal tubulointerstitial fibrosis of mice. Methods A model of renal tubulointerstitial fibrosis was established by the method of unilateral ureteral obstruction (UUO). The experimental mice were randomly divided into a drug-sham operation group (Sham+ S3I-201), a placebo-sham operation group (Sham+ Vehicle), a drug-model group (UUO+ S3I-201), and a placebo-model group (UUO+ Vehicle). The four groups were administered intraperitoneally with S3I-201 solution (drug) or 0.05% DMSO PBS (placebo), once daily. Kidney specimens were taken on the 7th day of modeling, and collagen deposition was assessed by Masson staining and color area measurement algorithm. The qRT-PCR method was used to detect the mRNA expression of chemokine C-X-C-motif ligand 16 (CXCL16), interleukin-1β (IL-1β), intercellular adhesion molecule-1 (ICAM-1), transforming growth factor-β (TGF-β), and tumor necrosis factor-α (TNF-α), while immunohistochemical staining and immunoblotting methods were used to detect the protein expression of platelet-derived growth factor receptor β (PDGFRβ) in the obstructed kidneys. Results Renal interstitial collagen deposition was significantly higher in the placebo-model group (UUO+ Vehicle) than in the placebo-sham operation group (Sham+ Vehicle) (P<0.05). The mRNA expression of CXCL16, IL-1β, ICAM-1, TGF-β, and TNF-α were also significantly higher in the placebo-model group (UUO+ Vehicle) than in the placebo-sham operation group (Sham+ Vehicle) (P<0.05). The protein expression of PDGFRβ was significantly higher in the placebo-model group (UUO+ Vehicle) than in the placebo-sham operation group (Sham+ Vehicle) (P<0.05). After S3I-201 treatment for 7 days, the above indexes were significantly lower in the drug-model group (UUO+ S3I-201) than in placebo-model group (UUO+ Vehicle). Conclusion S3I-201 had a renal protective effect by inhibiting mRNA expression of various cytokines, decreasing protein expression of PDGFRβ, and reducing renal interstitial inflammation in mice with experimental tubulointerstitial fibrosis. Key words: Fibrosis; Unilateral ureteral obstruction; Signal transducers and activators of transcription; S3I-201