Exogenous pancreatic kininogenase protects against renal fibrosis in rat model of unilateral ureteral obstruction

  • Acta Pharmacol Sin. 2020 Dec;41(12):1597-1608. doi: 10.1038/s41401-020-0393-7.
Ji-Zhe Jin  1 ,  Hui-Ying Li  1  2 ,  Jian Jin  1 ,  Shang-Guo Piao  1 ,  Xiong-Hu Shen  3 ,  Yan-Ling Wu  4 ,  Jia-Chong Xu  5 ,  Long-Ye Zhang  1 ,  Yu-Ji Jiang  1 ,  Hai-Lan Zheng  1 ,  Ying-Shun Jin  1 ,  Sheng Cui  1 ,  Kang Luo  1 ,  Yi Quan  1 ,  Can Li  6
Affiliations
  • 1. Department of Nephrology, Yanbian University Hospital, Yanji, 133000, China.
  • 2. Postdoctoral Research Institute, Yanbian University Hospital, Yanji, 133000, China.
  • 3. Department of Oncology, Yanbian University Hospital, Yanji, 133000, China.
  • 4. Department of Pharmacology, Yanbian University, Yanji, 133000, China.
  • 5. Animal Care Institute, Yanbian University, Yanji, 133000, China.
  • 6. Department of Nephrology, Yanbian University Hospital, Yanji, 133000, China. [email protected].
PMID: 32300244 DOI: 10.1038/s41401-020-0393-7
Abstract

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 and cAMP in kidney tissues. Coadministration with either B1R antagonist (des-Arg9-[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.

Keywords
apoptosis; autophagy; kallikrein; oxidative stress; renal fibrosis.
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