Skip Navigation LinksHome > August 27, 2014 - Volume 98 - Issue 4 > Serine Protease Inhibitor-6 Inhibits Granzyme B–Mediated Inj...
doi: 10.1097/TP.0000000000000237
Basic and Experimental Research

Serine Protease Inhibitor-6 Inhibits Granzyme B–Mediated Injury of Renal Tubular Cells and Promotes Renal Allograft Survival

Lau, Arthur1,2,3; Khan, Karim1,3; Pavlosky, Alex1,2,3; Yin, Ziqin1; Huang, Xuyan1; Haig, Aaron3; Liu, Weihua1,3; Singh, Bhagi1,4; Zhang, Zhu-Xu1,2,3,5; Jevnikar, Anthony M.1,2,3,5

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Background: Protease inhibitor 9 (PI-9) is an intracellular serpin that specifically inhibits granzyme B, a cytotoxic serine protease found in the cytosolic granules of cytotoxic T lymphocytes and natural killer cells. Enhanced cortical expression of PI-9 has been observed in kidney allografts with subclinical rejection, suggesting that the tubular epithelial cell (TEC) expression of this protein may have a protective role and attenuate overt allograft rejection.

Methods and Results: We demonstrate that TEC express SPI-6 protein, the murine homolog of PI-9, basally with a modest increase after cytokine exposure. Tubular epithelial cell expression of SPI-6 blocks granzyme B–mediated death because TEC from SPI-6 null kidneys have increased susceptibility to cytotoxic CD8+ cells in vitro. The role of SPI-6 was tested in a mouse kidney transplant model using SPI-6 null or wild type donor kidneys (H-2b) into nephrectomized recipients (H-2d). SPI-6 null kidney recipients demonstrated reduced renal function at day 8 after transplantation compared to controls (creatinine, 113±23 vs. 28±3 μmol/L; n=5; P<0.01), consistent with observed tubular injury and extensive mononuclear cell infiltration. Loss of donor kidney SPI-6 shortened graft survival time (20±19 vs. 66±33 days; n=8–10; P<0.001).

Conclusion: Our data show for the first time that resistance of kidney TEC to cytotoxic T-cell granzyme B–induced death in vitro and in vivo is mediated by the expression of SPI-6. We suggest that SPI-6 is an important endogenous mechanism to prevent rejection injury from perforin or granzyme B effectors and enhanced PI-9 or SPI-6 expressions by TEC may provide protection from diverse forms of inflammatory kidney injury and promote long-term allograft survival.

© 2014 by Lippincott Williams & Wilkins





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