Effect of GP130 small molecular inhibitor SC144 on renal interstitial fibrosis in mice with unilateral ureteral obstruction / 上海交通大学学报（医学版）

ABSTRACT

Objective: To investigate the effect of glycoprotein 130 (GP130) inhibitor SC144 on extracellular matrix accumulation and JAK2/STAT3 signaling pathway in unilateral ureteral obstruction (UUO) mouse model, and explore its mechanism. Methods: Eighteen female BALB/c mice were randomly divided into 3 groups i.e. sham group, UUO group and SC144 group. All mice were sacrificed at day 14 and kidneys were harvested for further analysis. The changes of renal tissue morphology and pathology were observed by H-E and Masson staining. The expression of α-smooth muscle actin (α-SMA) and infiltration of macrophage cells were assayed by immunohistochemical staining. The levels of collagen-I, collagen-IV, monocyte chemoattractant protein-1 (MCP-1), transforming growth factor-β (TGF-β) mRNA were analyzed by real-time PCR. The activation of JAK2 and STAT3 was measured by Western blotting. Results: There was a trend toward decreased renal tubular lesion and renal interstitial fibrosis in SC144 group (H-E, P=0.052; Masson, P=0.063). SC144 significantly inhibited the levels of α-SMA, type I/type IV collagen and TGF-β mRNA (all P<0.05). Compared with UUO group, the phosphorylation levels of JAK2 and STAT3 were significantly decreased in SC144 group (both P<0.05). Conclusion: The treatment of UUO mouse model with SC144 can inhibit the activation of α-SMA, attenuate the phosphorylation of STAT3, reduce extracellular matrix protein deposition following injury and renal tubular epithelial-mesenchymal transition (EMT) via JAK2/STAT3 signaling pathway, indicating its potential in attenuating interstitial fibrosis in obstructive nephropathy.