Role of JAK-STAT signaling in the interstitial fibrosis of unilateral ureter obstruction mice / 中华肾脏病杂志

ABSTRACT

Objective To study the role of JAK-STAT singal transduction pathway in the interstitial fibrosis of unilateral ureter obstruction (UUO)mice. Methods Mice UUO model was established and the phosphorylation of JAK-STAT was examined at day 1,4,7 and 14 after ligation of the ureter.Mice in the treatment group were treated with daily injection of selective JAK2 inhibitor AG490 starting 2 h before ureter ligation until sacrifice while vehicle alone was given to mice in the model control group.Mice were sacrificed at day 14 after the establishment of model.Renal tubular lesion and interstitial fibrosis were assessed on paraffin section.Immunohistochemistry was used to detect renal macrophage infihration and α-SMA expression.The expression of collagen Ⅲ and MCP-1 mRNA was measured by RT-PCR.Phosphorylation of JAK2and STAT1 was examined by Western blotting. Results JAK2-STAT1 signaling transduction pathway was activated in UUO model.The activation of JAK2-STAT1 was closely correlated with the progression of renal injury,tubular histological lesions and interstitial fibrosis.AG490 treatment significantly inhibited the phosphorylation of JAK2 and STAT1 (P＜0.01).AG490 treatment also significantly reduced tubular lesions[(21.7 ±1.7)% vs (49.4±1.0)%]and interstitial fibrosis(1.0±0.1 vs 2.3±0.2),α-SMA expression(0.9±0.1 vs 2.1±0.2)and maerophage accumulation[(13.3±1.6)cells/HPF vs (34.4±1.0)cells/HPF](all P＜0.01).In addition,AG490 significantly inhibited the expression of collagen Ⅲ and MCP-1 mRNA. Conclusion JAK-STAT signaling plays an important role in renal tubulointerstitial inflammation and fibrosis.