*Purpose: Prostaglandin E2 (PGE2) is generated from arachidonic acid via cyclooxygenase-2 (COX2) and is known to modulate the immune response via its receptors: EP1, EP2, EP3, and EP4. Receptors EP2 and EP4 are G_S-coupled and mediate the anti-inflammatory effects of PGE2 through a cAMP-dependent pathway. Receptors EP1 (G_i-coupled) and EP3 (G_q-coupled) mediate a pro-inflammatory response through the inhibition of cAMP and the release of intracellular Ca²⁺, respectively. Consequently, we set out to determine whether there was a correlation between COX2 and EP1-4 expression in renal allograft rejection using a porcine model.

*Methods: 29 pig kidney transplants were performed including allotransplants (n=17, no immunosuppression, all grafts with documented swine leukocyte antigen mismatches), autotransplants (n=5), and control right kidneys (n=7). Left kidneys were transplanted and right nephrectomy was performed at the time of the transplant. Pigs were sacrificed 72 hours post-transplant and nephrectomy was performed. Rejection was assessed by Banff criteria. Renal function was assessed pre- and post-operatively. Protein expression for COX2, EP receptors, and their downstream mediators was assessed using western blotting and immunohistochemical staining. PGE2 levels in tissue were assessed using ELISA.

*Results: Histologically, the grade of Banff rejection included IA, IB, IIA, IIB, and III. Serum creatinine was significantly increased in allotransplants compared to autotransplants (5.36 ± 5.09 mean+SD, vs 1.64 ± 0.91 mg/dL, respectively). COX2 expression decreased significantly with increased rejection and showed a strong negative correlation with Banff grade (p < 0.05; R = 0.8333). Similar significant negative correlations were observed in EP2 (R = 0.7837) and EP4 (R = 0.8611) expression with increasing Banff grade. The expression of the pro-inflammatory receptors EP1 and EP3 did not change with rejection. There was no significant change in the level of PGE2 present in tissue.

*Conclusions: COX2, EP2, and EP4 expression is downregulated in acute kidney rejection and negatively correlates with Banff histologic score. EP1 and EP3 expression remained unchanged despite variations in Banff grade. We would speculate that relative decrease in the expression of the anti-inflammatory EP2 and EP4 receptors compared to the inflammatory EP1 and EP3 receptors may play a role in immune suppression following kidney transplantation.

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