ET _A receptor activation contributes to T cell accumulation in the kidney following ischemia‐reperfusion injury

Abstract

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 ET _A receptor, but its contribution to renal T cell infiltration following renal IR injury is poorly understood. To test whether ET _A receptor activation promotes T cell infiltration of the kidney following IR injury, male C57 BL/6 mice were treated with the ET _A 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 ET _A 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.