Abstract
Acute rejection is a major risk factor for chronic allograft injury (CAI). Blood leukocytes interacting with allograft endothelial cells during acute rejection were suggested to contribute to the still enigmatic pathogenesis of CAI. We hypothesize that tissue transglutaminase (Tgm2), a multifunctional protein and established marker of M2 macrophages, is involved in acute and chronic graft rejection. We focus on leukocytes accumulating in blood vessels of rat renal allografts (Fischer-344 to Lewis), an established model for reversible acute rejection and CAI. Monocytes in graft blood vessels overexpress Tgm2 when acute rejection peaks on day 9 after transplantation. Concomitantly, caspase-3 is activated, suggesting that Tgm2 expression is linked to apoptosis. After resolution of acute rejection on day 42, leukocytic Tgm2 levels are lower and activated caspase-3 does not differ among isografts and allografts. Cystamine was applied for 4 weeks after transplantation to inhibit extracellular transglutaminase activity, which did, however, not reduce CAI in the long run. In conclusion, this is the first report on Tgm2 expression by monocytes in vivo. Tgm2 may be involved in leukocytic apoptosis and thus in reversion of acute rejection. However, our data do not support a role of extracellular transglutaminase activity as a factor triggering CAI during self-limiting acute rejection.
Highlights
Kidney transplantation is the only curative therapy for endstage renal disease
We investigate Transglutaminase 2 (Tgm2) mRNA and protein expression by mononuclear blood leukocytes isolated from Lewis to Lewis isografts and F344 to Lewis allografts and by respective renal tissue Tgm2 expressions compared to activated caspase-3, a protease critically involved in apoptosis [26]
In agreement with the previously published data, we observed a strong increase in the number of mononuclear leukocytes accumulating in the vasculature of allografts on day 9 compared to isografts
Summary
Kidney transplantation is the only curative therapy for endstage renal disease. transplantation is limited by organ shortage and by its unfavorable long-term success due to chronic allograft injury (CAI) [1, 2]. A majority of blood leukocytes in day 9 allografts are monocytes displaying a unique state of partial activation regarding cell surface antigen and cytokine expression [9] These cells interact with graft endothelial cells and might trigger CAV, which is characterized by intimal hyperplasia. To identify factors contributing to the pathogenesis of CAI during reversible acute rejection, we compared the transcriptome of mononuclear leukocytes isolated from renal allografts to isografts 9 days after transplantation. In this gene array experiment, tissue transglutaminase (transglutaminase 2, Tgm2) was found among the genes, which were upregulated by mononuclear leukocytes accumulating in the lumina of allograft blood
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