ETA receptor activation contributes to T cell accumulation in the kidney following ischemia-reperfusion injury.

Renal ischemia-reperfusion (IR) injury and acute kidney injury (AKI) increase the risk of developing hypertension, with T cells suspected as a possible mechanistic link. Endothelin promotes renal T cell infiltration in several diseases, predominantly via the ETA receptor, but its contribution to renal T cell infiltration following renal IR injury is poorly understood. To test whether ETA receptor activation promotes T cell infiltration of the kidney following IR injury, male C57BL/6 mice were treated with the ETA receptor antagonist ABT-627 or vehicle, commencing 2 days prior to unilateral renal IR injury. Mice were sacrificed at 24 h or 10 days post-IR for assessment of the initial renal injury and subsequent infiltration of T cells. Vehicle and ABT-627-treated mice displayed significant upregulation of endothelin-1 (ET-1) in the IR compared to contralateral kidney at both 24 h and 10 days post-IR (P < 0.001). Renal CD3+ T cell numbers were increased in the IR compared to contralateral kidneys at 10 days, but ABT-627-treated mice displayed a 35% reduction in this effect in the outer medulla (P < 0.05 vs. vehicle) and a nonsignificant 23% reduction in the cortex compared to vehicle-treated mice. Whether specific T cell subsets were affected awaits confirmation by flow cytometry, but outer medullary expression of the T helper 17 transcription factor RORγt was reduced by ABT-627 (P = 0.06). These data indicate that ET-1 acting via the ETA receptor contributes to renal T cell infiltration post-IR injury. This may have important implications for immune system-mediated long-term consequences of AKI, an area which awaits further investigation.