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

Collapse Box


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





Article Tools


Article Level Metrics

Search for Similar Articles
You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search.