Lack of an apparent role for endothelin‐1 in the prolonged reduction in renal perfusion following severe unilateral ischemia‐reperfusion injury in the mouse

Therapeutic approaches to block the progression from acute kidney injury to chronic kidney disease are currently lacking. Endothelin‐1 (ET‐1) is a powerful vasoconstrictor, induced by hypoxia, and previously implicated in renal ischemia‐reperfusion (IR) injury. This study tested the hypothesis that blunting the vascular influence of ET‐1, either through endothelin ET(A) receptor blockade (ABT‐627) or vascular endothelial cell deletion of ET‐1 (VEET KO), would improve recovery of renal perfusion and repair of injury following a severe ischemic insult in mice (45 min unilateral renal ischemia). Male C57Bl/6 mice receiving vehicle or ABT‐627 commencing 2 days prior to surgery, and VEET KO mice and wild‐type littermates (WT) underwent 45 min unilateral renal IR surgery followed by 28 days recovery. Renal blood velocity was measured by pulsed‐wave Doppler ultrasound before and after surgery. Renal blood velocity was not significantly different between pairs of groups before surgery. Unilateral IR induced a marked reduction in renal blood velocity of the IR kidney at 24 h postsurgery in all groups, which partially recovered but remained below baseline at 28 days post‐IR. Despite the lack of effect on renal blood velocity, ET(A) receptor blockade significantly attenuated the atrophy of the post‐IR kidney, whereas this was not significantly affected by lack of endothelial ET‐1 expression. These data suggest that although blockade of the ET(A) receptor is mildly beneficial in preserving renal mass following a severe ischemic insult, this protective effect does not appear to involve improved recovery of renal perfusion.