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Tissue kallikrein has protective function against various types of injury.In this study,we investigated whether exogenous pancreatic kininogenase (PK) conferred renoprotection in a rat model of unilateral ureteral obstruction (UUO) and H2O2-treated HK-2 cells in vitro.SD rats were subjected to UUO surgery,then PK (7.2 U/g per day,ip) was administered for 7 or 14 days.After the treatment,rats were euthanized;the obstructed kidneys were harvested for further examination.We found that PK administration significantly attenuated interstitial inflammation and fibrosis,and downregulated the expression of proinflammatory (MCP-1,TLR-2,and OPN) and profibrotic (TGF-β1 and CTGF) cytokines in obstructed kidney.UUO-induced oxidative stress,closely associated with excessive apoptotic cell death and autophagy via PI3K/AKT/FoxO1a signaling,which were abolished by PK administration.We further showed that PK administration increased the expression of bradykinin receptors 1 and 2 (B1R and B2R) mRNA and the production of NO andcAMP in kidney tissues.Coadministration with either B1R antagonist (des-Argg-[Leu8]-bradykinin) or B2R antagonist (icatibant) abrogated the renoprotective effects of PK,and reduced the levels of NO and cAMP in obstructed kidney.In H2O2-treated HK-2 cells,addition of PK (6 pg/mL) significantly decreased ROS production,regulated the expression of oxidant and antioxidant enzymes,suppressed the expression of TGF-β1 and MCP-1,and inhibited cell apoptosis.Our data demonstrate that PK treatment protects against the progression of renal fibrosis in obstructed kidneys.